OBJECTIVES: The objective of this study was to estimate the effectiveness of varenicline, bupropion and nicotine replacement therapy (NRT) in smoking cessation in two specialized smoking units belonging to primary care centers. METHODS: A multicenter longitudinal observational study was designed. Patient’s data were collected retrospectively based on their clinical records. Patients over the age of 18, who initiated treatment of smoking cessation between January 1, 2006 and January 12, 2008 with varenicline, bupropion or NRT were included in the analysis. Patient’s follow-up was conducted from time-baseline (day 1) and assessed at 6 and 12 months. Main variables included in the study were: comorbidities, effectiveness (continuous abstinence) and pharmacological tolerability. Statistical analysis was performed by Kaplan-Maier survival curves; p<0,05. RESULTS: A total of 957 smokers patients treated with NRT (53.0%), bupropion (25.1%) and varenicline (21.9%) were included in the analysis. The mean age of participants was 47.6 (11.3) years and 58.6% were men. The average duration of smoking was 19.5 (6.7) years. At 6 months, 61.2% (95% CI: 54.6-67.8%) of participants in the varenicline group were continuously abstinent from smoking compared with 56.9% (95% CI: 50.6-63.2%) in the bupropion group and 52.3% (95% CI: 48.0-56.6%) in the NRT group; p = 0.003. At 12 months, the rate of continuous abstinence was 57.4% (95% CI: 50.7-64.1%) in the varenicline group compared with 52.9% (95% CI: 46.6-59.2%) in the bupropion group and 47.1% (95% CI: 42.8-51.4%) in the NRT group; p = 0.002. Pharmacological tolerability was similar between groups except for symptoms of irritability which were lower in the varenicline group: 4.3% compared to 8.3% in the bupropion group and 10.3% in the NRT group. CONCLUSIONS: Varenicline appeared to be an effective and safety alternative compared with bupropion and NRT on smoking cessation in the primary care setting.