ABSTRACTBackground: Varenicline is an effective smoking cessation therapy in clinical trials. However, its effectiveness might vary in a real world setting and its long term effectiveness (2-year) has not been reported yet. Objective: The objective was ascertaining the effectiveness of varenicline in the treatment of tobacco consumption in Primary Care settings. Methods: Observational, multicenter, retrospective study using medical records of smokers followed for 24 months. Sociodemographic characteristics, comorbidity, type of treatment (varenicline with or without group therapy), and smoking characteristics (Fageström and Richmond tests, starting age, number of cigarettes, cessation attempts, and initial CO-oximeter measurements) were evaluated. Results: 773 smokers treated with varenicline (72.4%) or varenicline combined with group therapy (27.6%) were included. Mean age was 43.6 years [51.7% male (n = 400)]. Continuous abstinence rate at 24 months was 44.4%, with no significant gender or age differences. Median cessation time was 398 days (95%CI: 376–421). A clear association was detected between the probability of remaining abstinent at 24 months and participation in group therapy (OR: 1.877, 95%CI: 1.362–2.589), as well as treatment adherence (compliance >80%) (OR: 6.556, 95%CI: 5.870–7.242), but not with co-financing of treatment (observed in 77% of patients). For every day that varenicline was taken, abstinence increased by an average of 6.6 days. Conclusions: This retrospective cohort study suggests that 2-year effectiveness of varenicline might be substantial in a real world setting. The abstinence rate was higher for those who also receive group therapy.