Despite effective therapies for smoking cessation, most smokers find quitting difficult and most successful quitters relapse. Considerable evidence supports a genetic risk for nicotine dependence; however, less is known about the pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation of the efficacy of varenicline and bupropion, we examined whether genes important in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict medication efficacy and adverse events. Subjects participated in randomized, double-blind, placebo-controlled smoking cessation clinical trials, comparing varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary analysis included 1175 smokers of European ancestry, and 785 single nucleotide polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins (genes included nAChR subunits, additional varenicline-specific genes, and genes involved in nicotine or bupropion metabolism). For varenicline, continuous abstinence (weeks 9–12) was associated with multiple nAChR subunit genes (including CHRNB2, CHRNA5, and CHRNA4)(OR= 1.76; 95% CI: 1.23–2.52)(p< 0.005); for bupropion, abstinence was associated with CYP2B6 (OR= 1.78; 95% CI: 1.27–2.50)(p< 0.001). Incidence of nausea was associated with several nAChR subunit genes (OR= 0.50; 95% CI: 0.36–0.70)(p< 0.0001) and time to relapse after quitting was associated with HTR3B (HR= 1.97; 95% CI: 1.45–2.68)(p< 0.0001). These data provide evidence for multiple genetic loci contributing to smoking cessation and therapeutic response. Different loci are associated with varenicline vs bupropion response, suggesting that additional research may identify clinically useful markers to guide treatment decisions.