This project answers many prominent but largely unanswered calls over the last decade to address tobacco dependence in persons with mental health disorders, especially major depressive disorder (MDD). Upwards of 43% of persons with MDD are daily smokers who are more likely to smoke heavily, show greater tobacco dependence, suffer more severe withdrawal, and experience lower quit rates than smokers without MDD. Very little is known about treatment strategies that might optimize smoking cessation for smokers with MDD because almost all randomized clinical trials have excluded these smokers. We conducted a meta-analysis of 42 randomized clinical trials (RCTs) comprising nearly 3000 smokers with past MDD given that these data were routinely collected and offer insight into potential treatment approaches for patients with current or recent MDD. Results showed that CBT mood management (CBT MM) and varenicline individually had the strongest associations with short-term abstinence. Varenicline also had the strongest association with long-term abstinence. Behavioral activation (BA) is simpler to administer and easier for patients to understand than CBT MM and therefore may enhance skill acquisition/retainment and long-term abstinence. The goal of BA is to increase engagement in rewarding activities, a problem for smokers with MDD who find smoking especially rewarding and prefer it over many other traditionally rewarding activities, by reducing patterns of avoidance, withdrawal, and inactivity. Combination treatment with BA and varenicline has great potential to improve long- term abstinence rates for smokers with current or recent MDD because it addresses the unique psychological factors that may maintain their tobacco dependence. This proposed double-blind, placebo-controlled, randomized trial will evaluate the efficacy of BA plus varenicline for treating tobacco dependence in smokers with current or recent (past year) MDD. Six hundred and thirty daily (e5 cigarettes/day) smokers with at least moderate depressive symptoms will be randomized to receive 12 weeks of one of four treatments: 1) Standard behavioral cessation treatment (ST) + placebo; 2) BA integrated with ST (BA) + placebo; 3) ST + varenicline; or 4) BA + varenicline. Both BA and ST will be administered in eight 1-hour sessions, occurring weekly for the first four weeks and biweekly for the final eight weeks. Randomization will be stratified on clinical site (Northwestern, PENN), gender, and severity of depressive symptoms (moderate vs. severe). The primary outcomes will be carbon monoxide (CO) verified 7-day point prevalence abstinence at 24-weeks post-quit. Additional aims include assessing adverse event rates between varenicline and placebo arms, and testing for mediation of treatment effects by anhedonia, cognitive function (attention and memory), cigarette reward value, and craving and withdrawal. This will be the first adequately powered trial of BA for smoking cessation in this population; the first RCT to evaluate varenicline among a community sample of smokers with MDD; and the first RCT to assess the main and combined effects of these two treatments.