James Cameron has spent 15 years and reportedly around $230 million making Avatar, and if you consider additional costs like marketing ($150 million minimum), the price tag might ultimately reach around $500 million. In a rough breakdown of the numbers, the New York Times concludes the film will need to make $250 million at the U.S. box office before the studio and its partners are "headed into the black."
To put that in perspective, only five films this year have crossed the $250 million mark: Star Trek, Transformers: Revenge of the Fallen, Up, Harry Potter and the Half-Blood Prince and The Hangover. The good news for Cameron is that three of those were sci-fi or fantasy (four if you include Up). The bad news is, they're all based on existing franchises, unlike Avatar.
There were also a lot of high-profile sci-fi films that didn't break even the (relatively) paltry $200 million mark, like X-Men Origins: Wolverine, Monsters vs. Aliens, Watchmen and the independent phenomenon District 9. So there is no guarantee Avatar will reach the $250 million mark, and it's not clear if it will be profitable even if it does.
Cameron has been in this position before, with his worldwide blockbuster Titanic. At one point that film seemingly had no chance of making money, and Cameron had even given up not only his potential share of profits but also his salary to help cover its costs. He made out okay after Titanic became the highest-grossing film in history, however.
In a similar move, Cameron's share of any Avatar profits will be reduced if the production budget goes over a certain amount. Which seems like a moot point, because if it doesn't do extremely well there will be no profits to share, but if it does there will probably enough to go around.