DESCRIPTION (investigator's abstract): Four hundred adult smokers will be enrolled in the study. The primary goal is to compare 2 strategies designed to promote longer-term maintenance of smoking cessation. Each strategy will include an acute treatment phase and a maintenance treatment phase. All smokers will receive the same "Acute Phase Treatment." In this acute phase, all smokers will receive treatment for nicotine dependence that combines nicotine patch (21mg), bupropion (300mg), and relapse prevention training (RPT). During the acute phase, nicotine patch will be provided for a total of 8 weeks and bupropion and RPT will be provided for a total of 9 weeks. Following the acute treatment phase, participants will enter a "Maintenance Treatment Phase." During maintenance treatment, half of the participants (n=200) will receive an additional 16 weeks of therapy with bupropion. The other half (n=200) will receive matching placebo. Primary hypothesis: Participants who receive bupropion during the maintenance treatment phase will have a higher abstinence rate at l2mo follow-up than participants assigned to receive matching placebo. Abstinence will be defined as a report of non-smoking (not even a puff) for 7 consecutive days prior to contact plus a saliva cotinine level below 20 ng/ml. With 200 participants per cell, we will have, in general, 80 percent power at a 2-tailed alpha of .05 to detect a difference in abstinence rates of at least 15 percent over a large range of success probabilities. Secondary objectives: we propose to genotype all subjects for polymorphisms at loci hypothesized to affect nicotine dependence and/or bupropion efficacy. These include CYP2D6, the serotonin transporter, the dopamine transporter, dopamine D2 receptor, and the dopamine D4 receptor. Analyses will examine whether polymorphisms at these loci moderate response to treatment. The proposed study will address several important gaps in our knowledge. First, our proposed study would be perhaps the first to evaluate the efficacy of an antidepressant medication as maintenance therapy in the treatment of nicotine dependence. Second, this study would be among the first to examine the efficacy of a treatment for nicotine dependence combining nicotine replacement and antidepressant medication. Third, to our knowledge this may be the first prospective trial of smoking cessation techniques in which genetic data are included as predictors of outcome. In general, this study will provide important practical information to the medical and health communities concerning the utility of longer-term therapy with antidepressant medication for smoking cessation and will advance our knowledge of the underlying relationship of nicotine addiction and depression.