Among smokers, women may be at greater risk than men for developing smoking-related diseases, perhaps because they have greater difficulty quitting smoking, as suggested by numerous studies. In the present study, we hypothesized that bupropion would reduce this gender disparity among 314 women and 241 men enrolled in a placebo-controlled, randomized trial using behavioral counseling plus 10 weeks of bupropion (300 mg). Prolonged abstinence and biochemically verified point prevalence outcomes were measured at end of treatment (8 weeks after the quit date) and at 6-month follow-up. A logistic regression model of 6-month prolonged abstinence and a Cox regression (survival analysis) model revealed a significant gender by smoking rate by drug interaction and a main effect for marital status. This three-way interaction suggests that bupropion particularly benefited men who smoked more than one pack of cigarettes per day at baseline and, conversely, women who smoked a pack or less. The point prevalence logistic regression model showed no evidence that either gender or smoking rate modified the effect of treatment. These results suggest that bupropion treatment may reduce the gender disparity in prolonged abstinence rates among lighter smokers.