OBJECTIVES: The aim of this study was to compare efficacy and safety of varenicline compared with placebo, nicotine replacement therapy or sustained-release bupropion for smoking cessation in adults. METHODS: Systematic review of randomized controlled trials was performed to assess clinical effectiveness of varenicline according to guidelines of Cochrane Collaboration and HTA Agency in Poland. RESULTS: The clinical effectiveness analysis of varenicline compared with placebo for smoking cessation in adults showed statistically significant difference between groups in continuous abstinence. Abstinence rate for weeks 9 through 12, 9 through 24 and 9 through 52 was superior for varenicline vs placebo. The clinical effectiveness analysis of varenicline in smoking adults in the context of maintaining their abstinence showed significantly greater continuous abstinence rate in weeks 13 to 24 compared with placebo. This advantage was maintained through the follow-up to week 52. The clinical effectiveness of varenicline compared with NTZ for smoking cessation in adults showed that continuous abstinence rate for the last 4 weeks of 12 weeks treatment was significantly greater for varenicline (55.9%) than NRT (43.2%). In clinical effectiveness analysis of varenicline compared with BP, varenicline was found to be more efficacious in continuous abstinence rates. For weeks 9 through 12, the odds ratio was 1.86(95% CI: 1.49; 2.33); for weeks 9-24 OR: 1.65(95% CI: 1.29; 2.11); for weeks 9-52 OR: 1.59(95% CI: 1.21; 2.10). CONCLUSIONS: The performed analysis shows that varenicline is effective therapy for smoking cessation. Varenicline was more efficacious than placebo, NTZ and bupropion SR at continuous smoking abstinence outcomes for the last 4 weeks of study, from weeks 9 through 24 and weeks 9 through 52. Varenicline more often than placebo, NTZ and bupropion SR causes nausea, insomnia, abnormal dreams and headache. Varenicline more effectively reduces urge to smoke, depressed mood, anxiety and smoking satisfaction.