The study was a randomized placebo-controlled trial testing whether fluoxetine selectively enhances cessation for smokers with a history of depression. Euthymic smokers with (H+, n = 109) or without (H-, n = 138) a history of major depression received 60 mg fluoxetine or placebo plus group behavioral quit-smoking treatment for 12 weeks. Fluoxetine initially enhanced cessation for H+ smokers (p = 0.02) but subsequently impaired cessation regardless of depressive history. Six months after quit date, fluoxetine-treated participants were 3.3 times more likely to be smoking (p = 0.02). Further research is warranted to determine why high-dose fluoxetine produces continuing effects that oppose tobacco abstinence.