BACKGROUND A past history of major depression or alcoholism has been associated with poorer smoking treatment outcomes. AIM To evaluate the efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism, and changes in depressive symptoms during smoking abstinence. METHOD Data were drawn from a multicentre trial of bupropion for smoking cessation. Smokers (n = 615) received placebo or bupropion sustained-release at 100, 150, or 300 mg/day for six weeks after target quit date (TQD). The primary outcome was the point prevalence smoking abstinence at the end of treatment and at one year. The Beck Depression Inventory (BDI) was used to assess depressive symptoms. RESULTS A significant dose-response effect of bupropion for smoking cessation was found. This was independent of history of major depression or alcoholism. Among those continuously abstinent from smoking for two weeks following TQD, an increase in BDI score was associated with a return to smoking at end of treatment. CONCLUSIONS Bupropion is efficacious for smoking cessation independently of a former history of major depression or alcoholism. Increases in depressive symptoms during an initial period of abstinence are associated with a return to smoking.