Why did Osmosis Jones bomb?

Solution
The movie had an identity crisis making it impossible to market. Before it came out the stars of the movie promoted it on every talk show appearance for years, since animation takes so long to make. The live action parts were directed by the Farrelly brothers who did rated R comedies for adults and at the time animation in theaters was strictly a kids audience. Pixar and Dreamworks made CG the hot new thing and quickly killed 2D animation at the box office, so Osmosis Jones just wasn't on anybody's radar when it came out.
It was a cartoon out of Warner Bros.' feature animation division, which had literally one successful film (Space Jam), run by incompetent executives who know fuck-all regarding how to produce, or even market an animated film. You do the math.

Tellingly, even their best film, The Iron Giant, only came out as the movie we know and love because the execs realized what a mistake micromanaging production was after they killed Quest for Camelot creatively and financially. And even then, they completely botched the marketing.
 
The movie had an identity crisis making it impossible to market. Before it came out the stars of the movie promoted it on every talk show appearance for years, since animation takes so long to make. The live action parts were directed by the Farrelly brothers who did rated R comedies for adults and at the time animation in theaters was strictly a kids audience. Pixar and Dreamworks made CG the hot new thing and quickly killed 2D animation at the box office, so Osmosis Jones just wasn't on anybody's radar when it came out.
 
Solution
It's a shame OJ was a box-office failure, as the concept itself is beyond brilliant and lends itself to an almost endless well of ideas. Think about it - in how many ways can the average human body go "wrong"? While no one person will (probably) suffer hundreds of distinct ailments in his or her lifetime, that could've easily been sold as a believable conceit, like FTL travel in sci-fi shows. Cells at Work is basically the Japanese take on OJ and look at how popular it's become.

Chris Rock is, unfortunately, a very polarizing comic, especially when it comes to his vocal delivery. You tend to either love his speech mannerisms or it's akin to nails on a blackboard. I personally think it works quite well for OJ, but can understand that he's not everyone cup o' tea.

I've only seen a few episodes of the series, but if you sit down and really pay attention to the movie, it is LOADED with all sorts of terrific biological metaphors and puns. It's actually a really smart script. I'm not sure if the live-action segments with Murray helped or hindered it in the end, as some of the stuff the movie has Bill doing is truly gross, like the self-exploding zit scene, but a lot of it is also genuinely funny.

I realize this doesn't answer the OP's question, but I can't help myself but champion OJ whenever I see it mentioned.
 
Pixar and Dreamworks made CG the hot new thing and quickly killed 2D animation at the box office, so Osmosis Jones just wasn't on anybody's radar when it came out.
I really don't think 3D killed 2D in theaters. I think 2D killed itself. Just as we still see plenty of 2D work on television, I think 2D (American) theatrical works could still be a thing. But there was a string of 2D "failures" for various reasons around the time 3D started to take off (Osmosis Jones was one of those) and rather than learn the real reason Pixar was eating everyone else's lunch (compelling and heartfelt stories) they thought it must just be that kids won't sit still for 90 minutes of 2D animation anymore or whatever. I'd really like to see 2D make a resurgence, but the big studios are spooked and the smaller ones never really had the resources for it. Sad, many such cases.
 
I really don't think 3D killed 2D in theaters. I think 2D killed itself. Just as we still see plenty of 2D work on television, I think 2D (American) theatrical works could still be a thing. But there was a string of 2D "failures" for various reasons around the time 3D started to take off (Osmosis Jones was one of those) and rather than learn the real reason Pixar was eating everyone else's lunch (compelling and heartfelt stories) they thought it must just be that kids won't sit still for 90 minutes of 2D animation anymore or whatever. I'd really like to see 2D make a resurgence, but the big studios are spooked and the smaller ones never really had the resources for it. Sad, many such cases.

Oh yeah the quality of writing and storytelling in the CG features was better. Pixar movies could be done in 2D and would still be classics. They just established a new visual brand while the 2D visual brand was in decline. Audiences weren't loving the late 90's Disney films that came after Lion King. Treasure Planet was one of the worst. Then Disney switched to CG for things like Chicken Little, which also sucked. Since Disney was the dominant 2D brand at the time, you could say they killed 2D.
 
Oh yeah the quality of writing and storytelling in the CG features was better. Pixar movies could be done in 2D and would still be classics. They just established a new visual brand while the 2D visual brand was in decline. Audiences weren't loving the late 90's Disney films that came after Lion King. Treasure Planet was one of the worst. Then Disney switched to CG for things like Chicken Little, which also sucked. Since Disney was the dominant 2D brand at the time, you could say they killed 2D.
Treasure Planet… Well, okay, that's another point. Around that time the industry also saw the success of anime and thought that they needed to keep up with the times by making their stuff more "adult" and adventurous. So you had Treasure Planet, Titan AE, Atlantis, The Road to El Dorado. And I didn't hate any of those (Titan AE is really flawed but some parts of it are just amazing, like the ice asteroid part) but it turns out it wasn't really where the market was at the time. Meanwhile Pixar's stuff could entertain both kids and adults and still keep things G-rated. Disney tried and in some ways succeeded with The Emperor's New Groove and The Princess and the Frog, but they didn't make money hand over fist like Toy Story 2 and Shrek, so surely the animation must be the problem, right?
 
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I saw Osmosis Jones at the FantAsia festival in Montreal around a month before the general theatrical release. It was alright, definitely one of those "how were they able to afford Bill Murray?" kind of movies. I mean, I know Bill Murray works for scale if he likes the project but all I remember about Bill Murray in Osmosis Jones was that he ate food off the ground at a county fair and got anthrax.
 
The live action acting was beyond terrible. The best part of the film by far was the animated buddy cop thriller. It's strange, almost like two totally different films with different directors. You have a crude buddy cop film that while ostensibly for kids, manages to keep adults entertained with its sly humor that manages to go above kids' heads without being offensive. On the other hand you have a movie about a father/daughter relationship on the rocks that is simultaneously too boring to entertain kids, but too obvious and stupid to entertain adults, almost like a Nickelodeon daytime film. Even if the acting was better, rewatching the movie as an adult is really unnerving. Bill Murray plays am absolute cunt. He's a shitty father that obviously neglects his daughter, almost to the point where a CPS a foster parent arc in the second and third acts wouldn't be out of place. The tonal whiplash is enough to snap your neck.
 
Another thing that probably needs to be mentioned is that Shrek pretty much obliterated all animated competitors at the domestic box office in the summer of 2001, tripling the gross of the next highest-grossing animated film that summer, Atlantis: The Lost Empire ($263M vs. $82.5M). Even though Osmosis Jones opened almost three months later, movie-goers who wanted to watch an animated film were still opting to see Shrek again.

Osmosis Jones also opened against American Pie 2 and faced strong competition from Rush Hour 2, the number 3 movie of summer 2001 which had opened only a week earlier.
 
Warner Bros at that point had given up on animation after the bomb of Quest for Camelot. So they really didn't spend much on marketing on this or the Iron Giant when it came to the cinema however Iron Giant did get a big marketing push when it came to video/DVD and seems to have been a hit in that market.
 
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