The authors examined whether serum fluoxetine levels influence behavioral treatment adherence and smoking cessation outcome. Nondepressed smokers (N = 989) from 16 centers were randomized on a double-blind basis to receive either fluoxetine (30 or 60 mg) or placebo plus 9 sessions of behavioral smoking cessation treatment. Fluoxetine and norfluoxetine blood levels were assayed 1 week after the quit date. Logistic regression was used to predict treatment completion and cessation outcome, controlling for gender, age, treatment site, and degree of nicotine dependence. Higher steady-state fluoxetine blood levels (fluoxetine + norfluoxetine) predicted less likelihood of dropping out, chi2(1, N = 820) = 3.9, p < .05, and more likelihood of being abstinent, chi2(1, N = 513) = 18.1, p < .001. Attaining a higher fluoxetine blood level improved the likelihood of completing behavioral treatment and increased the probability of achieving abstinence.