Type 2 diabetes mellitus and insulin resistance are associated with an increased risk of myocardial infarction (MI). Although differences exist in insulin sensitization among oral hypoglycemic drugs, it is unclear whether these differences translate into a differential risk of MI and whether differences exist among these drugs. We conducted a case-control study of first MI in a 5-county area during a 56-month period. The patients were those with type 2 diabetes mellitus hospitalized with a first MI and the controls were those with diabetes mellitus randomly selected from the same geographic area. Information on medication use and other clinical data were obtained by telephone interview. After adjustment for all confounders, the odds ratio for MI for current monotherapy with thiazolidinedione and monotherapy with metformin compared with monotherapy with sulfonylurea was 0.33 (95% confidence interval 0.12 to 0.92, p = 0.03) and 0.48 (95% confidence interval 0.27 to 0.82, p = 0.01), respectively. The addition of a thiazolidinedione, but not metformin, to sulfonylurea monotherapy was associated with a significant reduction in MI risk compared with sulfonylurea therapy alone. In conclusion, the use of insulin-sensitizing drugs is associated with a significantly reduced risk of MI compared with sulfonylurea use, and the addition of a thiazolidinedione to sulfonylurea monotherapy is associated with a lower risk of MI.