Objective: This research examined why smokers receiving combination medication for smoking cessation are more likely to quit smoking than are those who receive either single agent (monotherapy) or placebo. Method: Data were collected from 1,504 current smokers (58.2% women, 83.9% White; mean age = 44.67 years, SD = 11.08) participating in a cessation clinical trial who were randomized to 1 of 6 cessation pharmacotherapy conditions (placebo, nicotine patch, nicotine lozenge, bupropion, nicotine patch + nicotine lozenge, and bupropion + nicotine lozenge). Participants completed ecological momentary assessments 4 times a day, concerning 5 hypothesized mediators (negative affect, positive affect, craving, smoking expectations, and withdrawal) of pharmacotherapy effects. Medications were provided for 8-12 weeks post-quit along with 6 individual counseling sessions. Mediational paths were estimated via a novel Bayesian approach with estimation of multiple mediator models. Results: Biochemically confirmed 8-week abstinence was the outcome variable, with the monotherapy and combination pharmacotherapy composites producing 45% (n = 689) and 54% (n = 478) abstinence rates, respectively. The univariate models suggested that the combination treatments produced higher abstinence rates than the monotherapies because of greater suppression of withdrawal, craving, and smoking expectations. However, multiple mediator models showed that the suppression of craving on the quit day produced the strongest mediational effects and could account for the mediational effects of other tested variables. Conclusion: Suppression of craving on the quit day significantly mediates the clinical effects of monotherapies and combination smoking pharmacotherapies, and the higher abstinence rates for combination therapy versus monotherapies appear primarily due to greater craving suppression. (Contains 5 footnotes, 4 tables, and 1 figure.)