AIMS: To explore the impact of glucose lowering treatment on prognosis in diabetic patients with myocardial infarction. METHODS AND RESULTS: 1181 type 2 diabetic patients (mean age 68 years; 67% males) discharged after myocardial infarction were followed (median of 2.1 years). At discharge, 436 patients (37%) had oral glucose lowering agents whereof 268 sulphonylureas and 200 metformin, while 690 patients (58%) were on insulin. The impact of treatment was analysed by an updated Cox proportional hazards regression model, correcting for confounders. Cardiovascular mortality was not influenced by metformin [Hazard ratio (HR) 0.93, 95% CI 0.60-1.43; P = 0.73], sulphonylureas (HR 1.15, 95% CI 0.80-1.64; P = 0.45), or insulin (HR 1.05, 95% CI 0.75-1.46; P = 0.77). The risk for non-fatal myocardial infarction and stroke increased significantly in patients on insulin (HR 1.73, 95% CI 1.26-2.37; P = 0.0007), whereas this risk was lower among those on metformin (HR 0.63, CI 0.42-0.95; P = 0.03) and unchanged with sulphonylureas (HR 0.81, 95% CI 0.57-1.14; P = 0.23). This finding remained analysing only patients with newly instituted insulin and those randomly allocated to newly instituted insulin. CONCLUSION: Controlling for confounders including glycemic control, there was no significant difference in mortality between sulphonylureas, metformin, and insulin. In this post hoc analysis, the risk of non-fatal myocardial infarction and stroke increased significantly by insulin treatment while metformin was protective. It is emphasized that this observation is done in an epidemiological analysis and should encourage to further confirmation in randomized trials.