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Nick Naylor (played by Aaron Eckhart) is one of the most despised persons in the USA. He is the chief spokesman for the Academy of Tobacco Studies, a pseudo research facility sponsored by the big tobacco companies. His job is to "defend the defenseless", the multinational companies, by spinning the truth to fit their interests; and he's the best in it.

But that's just one side of Nick Naylor. On the other, he is the father of Joey, the son he has with his ex-wife Jill. Trying to be a better father and wanting to spend some time with his son, Nick takes Joey with him on a business trip to California, where he arranges product placement of cigarettes in Hollywood movies and persuades the cancer-stricken Marlboro Man Lorne Lutch not to turn against his former employers. Joey takes a lot of interest in what his dad is doing and their relationship tightens during the journey.

Yet at the trip's end, problems await Nick: First he gets kidnapped and almost killed by anti-smoking activists, then Heather Holloway (played by Katie Holmes), an attractive reporter he has been sleeping with secretly, publishes an article that views him as a heartless liar and reveals all his activities in California as well as his meetings with the M.O.D Squad.

After that - of course - he gets fired by his boss BR (played by J.K. Simmons), which leads to him falling into self-pity and hiding in his apartment.

Meanwhile, the Senator of Vermont, Ortolan Finistirre (played by William H. Macey), is planning to pass a bill that enforces a big "POISON" label with scull and crossbones on it. But Nick's son, who has started to become much like his dad, is able to pull Nick out of his misery; and Nick strikes back.

First he reveals his sexual affair with Heather to the media, which leaves her looking pretty unprofessional, and in the same press conference announces that he will be taking part at Senator Finistirre's congressional hearing. At the hearing, Nick does, what he is best at: he talks; and he does so well, BR wants him back. But Nick refuses his offer as an example to his son and founds his own public relations firm. Finally, the M.O.D Squad is still having its meetings, now with three new members from the fast foot, oil and hazardous waste lobbies.

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