Adult smokers (N = 253) without clinically significant depression were randomized on a double-blind basis to receive fluoxetine (30 or 60 mg daily) or a placebo for 10 weeks in combination with cognitive-behavioral therapy (CBT). It was predicted that fluoxetine would selectively benefit smokers with higher baseline depression, nicotine dependence, and weight concern and lower self-efficacy about quitting smoking. Among those who completed the prescribed treatment regimen, baseline depression scores moderated the treatment response. Logistic regression analyses showed that 1 and 3 months after the quit date, fluoxetine increased the likelihood of abstinence, as compared with placebo, among smokers with minor depression but not among those with little or no depression. Results suggests that, as an adjunct to CBT, fluoxetine enhances cessation by selectively benefiting medication-compliant smokers who display even subclinical levels of depression.