Background: Despite the fact that several pharmacotherapies have been evaluated to be effective measured by continuous abstinence rate, it is not clear which smoking cessation strategy is more effective in terms of providing a higher abstinence rate following cessation among obese smokers. The objective of this study was to compare abstinence rates of different Food Drug Administration (FDA)-approved smoking cessation medication strategies among obese smokers. Materials and Methods: A retrospective cohort study was conducted using the General Electric, electronic medical record database (2006-2011). The cohort consisted of obese adult smokers newly initiating the use of an FDA-approved smoking cessation medication (bupropion vs. varenicline). Multivariate logistic regression models were carried out to compare the abstinence between individuals prescribed bupropion versus varenicline at 3, 6, and 12 months after the treatment initiation. Multiple imputations were used to account for the missing data on covariates. Results: Descriptive analysis showed a slightly higher abstinence rate for those using bupropion compared to those using varenicline among obese smokers (bupropion vs. varenicline: 19.65% vs. 17.01%) at 3 months (P < 0.05); 22.39% vs. 20.58% at 6 months (P = 0.16); 24.15% versus 22.86% at 12 months (P = 0.28). After adjusting for the covariates, type of medications was not associated with better abstinence among obese patients. Conclusions: While previous literature among adults reports better abstinence with varenicline compared to bupropion, our findings among obese smokers indicate no difference in abstinence for those using bupropion compared to those using varenicline.