Context: African Americans disproportionately experience greater smoking attributable morbidity and mortality. Few clinical trials for smoking cessation in African Americans have been conducted, despite a different profile of both smoking and quitting patterns. Objective: To compare a sustained-release form of bupropion hydrochloride (bupropion SR) with placebo for smoking cessation among African Americans. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted from February 11, 1999, to December 8, 2000, of 600 African American adults treated at a community-based health care center. Volunteers, who smoked 10 or more cigarettes per day were recruited by targeted media and health care professionals. Intervention: Participants were randomly assigned to receive 150 mg of bupropion SR (n=300) or placebo (n=300) twice daily for 7 weeks. Brief motivational counseling was provided in-person at baseline, quit day, weeks 1 and 3, end of treatment (week 6), and by telephone at day 3 and weeks 5 and 7. Main Outcome Measures: Biochemically confirmed 7-day point prevalence abstinence at weeks 6 and 26 following quit day. Results: Using intention-to-treat procedures, confirmed abstinence rates at the end of 7 weeks of treatment were 36.0% in the bupropion SR group and 19.0% in the placebo group (17.0 percentage point difference; 95% confidence interval, 9.7-24.4; P<.001). At 26 weeks the quit rates were 21.0% in the treatment and 13.7% in the placebo groups (7.3 percentage point difference; 95% confidence interval, 1.0-13.7; P=.02). Those taking bupropion SR experienced a greater mean reduction in depression symptoms at week 6 (2.96 [9.45] vs 1.13 [8.84]) than those taking placebo, and after controlling for continuous abstinence, those taking bupropion SR also gained less weight than those taking placebo. Conclusions: Bupropion SR was effective for smoking cessation among African Americans and may be useful in reducing the health disparities associated with smoking.