OBJECTIVES: Comparative effectiveness of nicotine replacement therapy (NRT), bupropion and varenicline on smoking cessation remains unclear in clinical practice. Gender and nicotine dependence may alter effectiveness, as suggested in clinical trials. We compared the effectiveness of varenicline, NRT and bupropion in achieving abstinence among recent quitters in a large, prospective cohort. METHODS: In the nation-wide Smoking Cessation Program in Taiwan, 2012-2015, 11968 participants (mean age 44 [standard deviation 12.6] year, 83% men) received varenicline, NRT patch, NRT gum or bupropion, and self-reported the abstinence status at 1-week, 1-month and 6-month in phone interviews. Multivariable logistic regression modeling was performed to estimate the odds of abstinence comparing varenicline, NRT gum or bupropion to NRT patch. RESULTS: Among all participants, 5052 (85% men) received varenicline, 4149 (83% men) received NRT patch, 1944 (86% men) used NRT gum and 823 (80% men) used bupropion. Abstinence rates in 1-week, 1-month and 6-month were highest among varenicline users: 34%, 32% and 16%; for NRT patch, 26%, 24% and 12%; for NRT gum, 26%, 24% and 14%; and for bupropion, 23%, 21% and 10%; respectively. Overall, varenicline was associated with greater odds of abstinence compared with NRT patch, in 1-week (OR=1.30, 95% CI: 1.19-1.44), 1-month (OR=1.36, 95% CI: 1.24-1.50) and 6-month (OR=1.30, 95% CI: 1.14-1.47). Varenicline was also associated with 19%-40% higher odds of abstinence in 6 months, in men (OR=1.27, 95% CI: 1.11-1.45), women (OR=1.48, 95% CI: 1.05-2.10), smokers with severe dependence (OR=1.19, 95% CI: 1.00-1.42) or light/moderate dependence (OR=1.40, 95% CI: 1.17-1.67). Differential effectiveness between Bupropion, NRT gum and NRT patch was not observed. CONCLUSIONS: In smoking cessation clinics in Taiwan, varenicline was more effective than NRT patch to achieve abstinence. Contrary to findings from literature, varenicline may provide advantage over NRT patch in women and smokers with light/moderate dependence.