INTRODUCTION: Varenicline and bupropion sustained release (SR) are both safe and effective for the treatment of tobacco dependence and have different mechanisms of action. Combination pharmacotherapy with these agents may increase long-term smoking abstinence rates above what is observed with single-agent therapy. METHODS: We enrolled cigarettes smokers in an open-label, one-arm, Phase II clinical trial to obtain preliminary data on the potential effectiveness and safety of combination therapy with varenicline and bupropion SR for the treatment of tobacco dependence. Eligible subjects received varenicline titrated to 1.0 mg by mouth twice daily and bupropion SR titrated to 150 mg by mouth twice daily for a total of 12 weeks along with behavioral therapy. Self-reported smoking abstinence was biochemically confirmed with expired carbon monoxide. A total of 38 smokers with a mean age of 49.1 years (SD = 12.4) who smoked an average of 19.9 cigarettes/day (SD = 7.8) for 30 years (SD = 12.3) were enrolled. RESULTS: Seven-day point-prevalent smoking abstinence rates were 71% (95% CI = 54%-85%) at 3 months and 58% (95% CI = 41%-74%) at 6 months. Mean weight change during the medication phase among smoking-abstinent subjects was 1.6 kg (SD = 2.4). For both medications, 74% of subjects took at least 90% of the prescribed doses. The most common side effects were sleep disturbance (26%) and nausea (24%). No increase in depressive symptoms was observed, and no subjects reported suicidal ideation. DISCUSSION: Combination therapy with varenicline and bupropion SR may be effective for increasing smoking abstinence rates above that observed with monotherapy.