Aims: Spit tobacco use is prevalent in the United States and is associated with adverse health consequences. Health-care providers have neither evidence summaries nor evidence-based guidelines to assist them in treating patients who use spit tobacco. Design: We completed a systematic review of the literature to determine the efficacy and safety of pharmacological and behavioral interventions for the treatment of spit tobacco use. Findings: We found six randomized controlled trials testing pharmacological interventions and eight testing behavioral interventions. Using random-effects meta-analyses, bupropion sustained-release (SR) increased point prevalence tobacco abstinence at 12 weeks [odds ratio (OR) 2.1; 95% confidence interval (CI), 1.0-4.2]. Nicotine replacement therapy with patch or gum increased point prevalence tobacco abstinence at 6 months (OR 1.3; 95% CI, 1.0-1.6). Behavioral interventions increased long-term (6 month) point prevalence tobacco abstinence (OR 1.7; 95% CI, 1.1-2.9). Studies including an oral examination followed by feedback to the patient had the highest treatment effect. Conclusions: Behavioral interventions for ST users are effective for increasing ST abstinence rates. Bupropion SR is probably effective and nicotine replacement therapy may be effective. This evidence from randomized controlled trials provides health-care professionals with information necessary to effectively treat spit tobacco use.