This study evaluated a treatment combining bupropion with a novel acceptance and relationship focused behavioral intervention based on the acceptance and relationship context (ARC) model. Three hundred and three smokers from a community sample were randomly assigned to bupropion, a widely used smoking cessation medication, or bupropion plus functional analytic psychotherapy (FAP) and acceptance and commitment therapy (ACT). Objective measures of smoking outcomes and self-report measures of acceptance and relationship processes were taken at pretreatment, posttreatment, 6-month, and 1-year follow-up. The combined treatment was significantly better than bupropion alone at 1-year follow-up with 7-day point prevalence quit rates of 31.6% in the combined condition versus 17.5% in the medication-alone condition. Acceptance and the therapeutic relationship at posttreatment statistically mediated 12-month outcomes. Bupropion outcomes were enhanced with an acceptance and relationship focused behavioral treatment. (Contains 6 tables and 2 figures.)