Background: Drug therapy for tobacco abstinence has shown limited effect. Though Bupropion was tried in many studies to access the abstinence rate in smokers while limited data is available for smokeless tobacco (ST) users. This study is an attempt to assess the efficacy and safety of bupropion SR for tobacco abstinence among ST users. Methods: Adults using smokeless tobacco were randomized to bupropion SR titrated to 150 mg twice daily (N= 32) for 12 weeks. First assessment done at 6 week was the 7-day point-prevalence tobacco abstinence. Secondary outcomes were assessed at week 8 and week 12 in terms of prolonged and continuous tobacco abstinence rates, craving and nicotine withdrawal. Results: The prevalence of abstinence rates among smokeless tobacco users with bupropion SR at week 6 (28.1%), week 8 (28.1%) and week 12 (28.1%); p = 0.0003). The prolonged and continuous tobacco abstinence rates did not differ at weeks 6, 8, and 12. The treatment response was observed over time with FTND-ST scale. The mean (±SD) FTND-ST score change from baseline among abstinent subjects was a decrease of 2.66 (±1.52) for the bupropion SR group at 12 week. Conclusions: Abstinence rate with Bupropion SR showed significant increase among ST users. It also showed significant decrease in craving during treatment period.