Objectives: Combination therapy for tobacco dependence is becoming a standard of care. We sought to compare benefits and adverse events for combination therapy versus monotherapy for smokers in The Smokers' Health Project. Methods: This secondary data analysis was derived from adult smokers (n = 198) who initially smoked 15 or more cigarettes per day and participated in The Smokers' Health Project. Participants were grouped as taking 1 medication or 2 concurrent medications for tobacco dependence for 1 year over the 2- year study period. Adverse events were compared between medication groups using chi-square tests. Crude and adjusted odds ratios were calculated for cessation at 6, 12, 18, and 24 months using logistic regression. Results: No differences were seen in the proportion of incident adverse events between the monotherapy (28.3%) and combination therapy (32.3%) groups (P = 0.54). At 6 months, the odds of quitting were less in the combination therapy group relative to those taking monotherapy (adjusted odds ratio - 0.47 [95% CI 0.24-0.93]). At 12, 18, and 24 months, the odds of quitting did not differ between therapy groups (P = 0.07, 0.33, 0.55, respectively). Conclusion: Monotherapy and combination therapy for smoking cessation are similarly effective up to 24 months, and they exhibit similar adverse event attributes. (C) 2017 American Pharmacists Association (R) Published by Elsevier Inc. All rights reserved.