Objectives: This study sought to assess the determinants of platelet nitric oxide (NO) responsiveness in diabetic patients admitted with acute coronary syndromes (ACS) and the short-term effects of aggressive glycemic control on these factors. Background: Hyperglycemia is an independent risk factor for mortality in both diabetic patients and nondiabetic patients with ACS. The mechanism(s) underlying this observation and potential benefit from its correction remain uncertain. Although a reduction in NO bioavailability has been proposed, this remains untested in the ACS setting. Methods: A total of 76 diabetic patients with ACS were studied. Putative correlations between admission blood sugar level (BSL), inhibition of platelet aggregation by the NO donor sodium nitroprusside (SNP), and superoxide (O2-) were assessed. Hyperglycemic patients (n = 60) were randomized to acute glycemic control with intravenous versus subcutaneous insulin, and changes in the aforementioned parameters were compared. Plasma levels of the endogenous inhibitor of NO synthase asymmetric dimethylarginine (ADMA) were also monitored. Results: There was an inverse correlation between admission BSL and both platelet SNP response (p = 0.007) and ADMA levels (p = 0.045), and a positive correlation with O2- generation (p < 0.001). Intravenous insulin infusion resulted in a greater reduction (p < 0.001) in BSL, differentially improved platelet responsiveness to SNP (p = 0.049), and decreased O2- (p < 0.001) and ADMA levels (p = 0.049). Conclusions: A component of platelet dysfunction in diabetic patients with ACS is impaired responsiveness to the anti-aggregatory effects of NO, probably reflecting increased NO clearance by O2-. This phenomenon is reversed by acute aggressive glycemic control. These findings provide a further rationale for use of insulin therapy in acute myocardial infarction and suggest its extension to ACS patients.