Few pharmacological therapies have been shown to increase abstinence rates among spit tobacco (ST) users. Bupropion has been shown to be effective in increasing abstinence rates among smokers but has not been studied in ST users. Sixty-eight adult (aged > or = 18 years old) regular users of ST who were motivated to stop using ST were enrolled in a randomized, double-blind, placebo-controlled pilot study of bupropion sustained release (SR) or placebo for 12 weeks. The primary endpoint was 1-week, biochemically confirmed point-prevalence tobacco abstinence rate at the end of treatment (week 12). Nicotine withdrawal symptoms and weight change were assessed. At the end of 12 weeks of therapy, the point-prevalence tobacco abstinence rate was 44% in the bupropion group and 26% in the placebo group (p = 0.064). At 24 weeks following initiation of medication, the point-prevalence abstinence rate was 29% for both groups. After 7 weeks of medication, subjects on bupropion reported significantly less (p< or = 0.034) nicotine withdrawal than placebo. The mean weight change from baseline to end of treatment was +0.7 +/- 1.9 kg for bupropion and +4.4 +/- 2.4 kg for placebo (p = 0.03). The 6-month weight change for continuously abstinent subjects was 3.4 +/- 3.6 kg in the bupropion group and 6.2 +/- 5.0 kg in the placebo group (p = 0.49). Bupropion may increase abstinence rates in ST users and appears to attenuate weight gain during ST abstinence. Larger randomized, controlled trials of bupropion for ST users are needed.