OBJECTIVES: To compare abstinence rates of different Food and Drug Administration (FDA)-approved smoking cessation medication strategies among obese smokers. METHODS: A population-based retrospective cohort study was conducted using the General Electric (GE) electronic medical record database (2006 – 2011). The cohort consisted of obese adult smokers newly initiating use of an FDA-approved smoking cessation medication (bupropion vs. varenicline). The outcome variable was abstinent vs. not at 3, 6, or 12 months following first prescription. Descriptive analyses and chi-square tests were conducted to assess the frequency distribution of sample characteristics and their association with smoking cessation medication use. Multivariate logistic regression models were carried out to identify predictors of abstinence at 3, 6 and 12 months after assessing co-linearity between independent variables. Backward elimination was used to arrive at the final models. RESULTS: The abstinence rate of using any smoking cessation medications among obese smokers was 17.72% at 3 months, 20.61% at 6 months, and 22.51% at 12 months, respectively. While previous literature among adults reports higher abstinence rates with varenicline compared to bupropion, our findings among obese smokers indicate slightly higher abstinence rates for those using bupropion compared to those using varenicline (bupropion vs. varenicline: 20.51% vs. 16.85% at 3 months (p = 0.01); 22.87% versus 20.45% at 6 months (p = 0.09); 25.00% vs. 22.84% at 12 months (p = 0.10)). Significant predictors of successful abstinence included: demographic characteristic factors (age, race, region, payment type, and specialty group), diseases (hypertension, lung cancer, depression, and alcohol dependent), utilization (weight control drug use and number of cigarettes smoke per day), smoking counseling, and baseline Body Mass Index (BMI) value. CONCLUSIONS: Abstinence rates were higher among obese smokers taking bupropion vs. those taking varenicline. Predictors identified in this study should be considered when designing smoking cessation interventions among the high risk population of obese smokers.