Antihypertensive drugs are commonly prescribed for the treatment of patients with both diabetes and hypertension. However, the role of selected agents in the development of hypoglycemia remains controversial. The main objective of this study was to evaluate the effect of antihypertensive agents on the risk of hypoglycemia in diabetic patients receiving insulin or sulfonylurea therapy. A matched case-control study was conducted using Pennsylvania Medicaid data. Five control subjects, matched for sex and age, with no reported medical condition of hypoglycemia, were randomly selected for each case patient admitted for hypoglycemia in 1993, resulting in a total of 404 cases and 1375 controls. With these sample sizes, we were able to detect a difference of 10% (P < 0.05) for our primary outcome measure, hospitalization for hypoglycemia. The relative risk of hypoglycemia was estimated using an unconditional logistic regression. The risk of hypoglycemia was 5.5 times greater (95% confidence interval [CI], 4.0 to 7.6) in insulin versus sulfonylurea users and was not influenced by use of angiotensin-converting enzyme (ACE) inhibitors overall. However, use of the ACE inhibitor enalapril was associated with an increased risk of hypoglycemia (odds ratio, 2.4; 95% CI, 1.1 to 5.3) in sulfonylurea users, suggesting that analyzing the unintended side effects of a class of drugs can sometimes mask the adverse effects of individual drugs. Use of beta-blockers was not associated with an increased risk of hypoglycemia, providing further empiric evidence that beta-blockers are an appropriate treatment for persons with concomitant diabetes and hypertension. Per capita health care costs were approximately 3 times higher in patients hospitalized for hypoglycemia compared with controls (P < 0.05). Hospitalization for hypoglycemia is expensive and may be prevented with appropriate monitoring of diabetic patients taking selected antihypertensive agents such as enalapril.