Animal experimental data have shown that lipid-lowering agents reduce myocardial infarct size. This association has not been well studied in humans. We compared infarct size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n = 1,028) or were not (n = 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller infarcts than those who were not using these agents (median peak creatine kinase [CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p <0.0001). Similarly, in an unadjusted model, patients on previous lipid-lowering therapy were less likely to have a peak CK-MB >3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients [68.1%]; p <0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p <0.0001). In a covariate- and propensity-adjusted multivariable model, the association between pretreatment with lipid-lowering agents and smaller infarct size persisted (relative risk for CK-MB >3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p = 0.04). In conclusion, patients on lipid-lowering agents before an MI had significantly smaller infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes.