© 2016 The Authors. Background-Prior studies have found that smokers undergoing thrombolytic therapy for ST-segment elevation myocardial infarction have lower in-hospital mortality than nonsmokers, a phenomenon called the "smoker's paradox." Evidence, however, has been conflicting regarding whether this paradoxical association persists in the era of primary percutaneous coronary intervention. Methods and Results-We used the 2003-2012 National Inpatient Sample databases to identify all patients aged ≥18 years who underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Multivariable logistic regression was used to compare in-hospital mortality between smokers (current and former) and nonsmokers. Of the 985 174 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, 438 954 (44.6%) were smokers. Smokers were younger, were more often men, and were less likely to have traditional vascular risk factors than nonsmokers. Smokers had lower observed in-hospital mortality compared with nonsmokers (2.0% versus 5.9%; unadjusted odds ratio 0.32, 95% CI 0.31-0.33, P<0.001). Although the association between smoking and lower in-hospital mortality was partly attenuated after baseline risk adjustment, a significant residual association remained (adjusted odds ratio 0.60, 95% CI 0.58-0.62, P<0.001). This association largely persisted in age-stratified analyses. Smoking status was also associated with shorter average length of stay (3.5 versus 4.5 days, P<0.001) and lower incidence of postprocedure hemorrhage (4.2% versus 6.1%; adjusted odds ratio 0.81, 95% CI 0.80-0.83, P<0.001) and in-hospital cardiac arrest (1.3% versus 2.1%; adjusted OR 0.78, 95% CI 0.76-0.81, P<0.001). Conclusions-In this nationwide cohort of patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, we observed significantly lower risk-adjusted in-hospital mortality in smokers, suggesting that the smoker's paradox also applies to ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention.