OBJECTIVE: We sought to compare mortality reduction associated with secondary prevention in patients with and without diabetes after acute coronary syndrome (ACS). RESEARCH DESIGN AND METHODS: We conducted a cohort study involving 2,499 patients with ACS recruited from 11 U.K. hospitals. Multivariable analysis comparing all-cause mortality risk reduction associated with pharmacologic agents in patients with and without diabetes. RESULTS: Aspirin was not associated with significant mortality benefit in diabetes sufferers (95% CI 0.50-1.08); nondiabetic patients derived a 48% mortality reduction (P < 0.001). The interaction between diabetes and aspirin use was statistically significant (P = 0.037), indicating that patients with diabetes experience less effective mortality reduction from aspirin use. CONCLUSIONS: Aspirin, but not other secondary prevention agents, is associated with less effective mortality reduction in patients with diabetes and unstable coronary artery disease.