The use of angiotensin-converting enzyme (ACE) inhibitors early after an acute myocardial infarction to reduce mortality has been studied in several trials with inconsistent results. Aspirin (ASA) has become a well-documented therapeutic adjunct in patients with coronary heart disease. Attention has recently been focused on a possible interaction between ASA and ACE inhibitors. We therefore reanalyzed data from the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) to find any evidence of differential effects of the ACE inhibitor enalapril in subgroups defined by use of ASA at baseline. Logistic regression tested the multiplicative interaction. We used Rothman synergy index S, which would be equal to unity under additivity, and less than unity when suggesting antagonism, to examine the postulated interaction with departure from an additive model. Logistic regression showed that the enalapril-ASA interaction term was a significant predictor of mortality at the end of the study (p = 0.047), and was a borderline significant predictor of mortality 30 days after randomization (p = 0.085). The Rothman synergy index S was 0.66 (95% confidence interval 0.46 to 0.94) for mortality at the end of the study, and 0.68 ( 0.44 to 1.04) for 30-day mortality, indicating antagonism between enalapril and ASA with departure from an additive model. Thus, we found evidence of enalapril-ASA interaction. The effect of enalapril was less favorable among patients taking ASA than among patients not taking ASA at baseline.