© 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York. Objective We evaluated the relationship between aspirin supplementation and perinatal outcomes for potential effect modification by smoking status. Study Design A secondary analysis of two multicenter trials for which prophylactic aspirin supplementation was given to either low- or high-risk women for prevention of preeclampsia (PE). We examined the effect of aspirin by smoking status using the Breslow-Day test. Primary outcomes for this analysis were PE and preterm birth (PTB) < 37 weeks. We also examined PTB subtypes, small for gestational age (SGA), and neonatal intensive care unit (NICU) admission. Results The effect of prenatal aspirin on the risk of PE did not differ by smoking status (relative risk [RR] 95% confidence interval [CI] for smokers; RR 95% CI for nonsmokers) in low-risk (Breslow-Day p = 0.32) or high-risk (RR 95% CI for smokers; RR 95% CI for nonsmokers) (Breslow-Day p = 0.58) women. Among women at low risk for PE, the effect of aspirin supplementation on PTB was not different for nonsmokers (RR 1.00 [95% CI 0.8-1.3]) or smokers (RR 0.80 [95% CI 0.4-1.7]), (Breslow-Day p = 0.54). Aspirin was protective for PTB in nonsmokers (RR 0.80 [95% CI 0.7-0.9]), but not in smokers (RR 1.1 [95% CI 0.9-1.4]) in the high-risk group (Breslow-Day p = 0.03). Aspirin was also associated with increased spontaneous and early PTB and NICU admission in smokers and not nonsmokers in the high-risk group only. Conclusion Aspirin supplementation was associated with worse outcomes related to preterm birth in smokers in a high-risk but not low-risk cohort.