INTRODUCTION: Understanding the mechanisms by which bupropion promotes smoking cessation may lead to more effective treatment. To the extent that reduced smoking reinforcement is one such mechanism, a longer duration of pre quit bupropion treatment should promote extinction of smoking behavior. We evaluated whether 4 weeks of pre quit bupropion (extended run-in) results in greater pre quit reductions in smoking rate and cotinine and, secondarily, greater short-term abstinence, than standard 1 week of pre quit bupropion (standard run-in). METHODS: Adult smokers (n = 95; 48 females) were randomized to a standard run-in group (n = 48; 3-week placebo, then 1-week bupropion pre quit) or an extended run-in group (4-week pre quit bupropion; n = 47). Both groups received group behavioral counseling and 7 weeks of post quit bupropion. Smoking rate (and craving, withdrawal, and subjective effects) was collected daily during the pre quit period; biochemical data (cotinine and carbon monoxide) were collected at study visits. RESULTS: During the pre quit period, the extended run-in group exhibited a greater decrease in smoking rate, compared to the standard run-in group, interaction p = .03. Cigarette craving and salivary cotinine followed a similar pattern, though the latter was evident only among women. Biochemically verified 4-week continuous abstinence rates were higher in the extended run-in group (53%) than the standard run-in group (31%), p = .033. CONCLUSIONS: The extended use of bupropion prior to a quit attempt reduces smoking behavior during the pre quit period and improved short-term abstinence rates. The data are consistent with an extinction-of-reinforcement model and support further investigation of extended run-in bupropion therapy for smoking cessation.