In the Survival of Myocardial Infarction Long-term Evaluation (SMILE) 1, 3, and 4 studies, early administration of zofenopril in acute myocardial infarction showed to be prognostically beneficial versus placebo or ramipril. The SMILE-2 showed that both zofenopril and lisinopril are safe and showed no significant differences in the incidence of major cardiovascular (CV) complications. In this pooled analysis of individual data of the SMILE studies, we evaluated whether the superior efficacy of zofenopril is maintained also in patients with ≥1 CV risk factor (CV+, n = 2962) as compared to CV- (n = 668). The primary study end point was set to 1-year combined occurrence of death or hospitalization for CV causes. The risk of CV events was significantly reduced with zofenopril versus placebo either in the CV+ (-37%; hazard ratio: 0.63; 95% confidence interval: 0.51-0.78; P = 0.0001) or in the CV- group (-55%; hazard ratio: 0.45; 0.26-0.78; P = 0.004). Also, the other angiotensin-converting enzyme inhibitors reduced the risk of major CV outcomes, though the reduction was not statistically significant versus placebo (CV+: 0.78; 0.58-1.05; P = 0.107; CV-: 0.71; 0.36-1.41; P = 0.334). The benefit was larger in patients treated with zofenopril than other angiotensin-converting enzyme inhibitors, with a statistically significant difference for CV+ (0.79; 0.63-0.99; P = 0.039) versus CV- (0.62; 0.37-1.06; P = 0.081). In conclusion, zofenopril administered to patients after acute myocardial infarction has a positive impact on prognosis, regardless of the patient's CV risk profile.