OBJECTIVE: To quantify the risk for the occurrence of hyperglycemia requiring initiation of therapy among patients taking various antihypertensive regimens. DESIGN: Case-control study. SETTING: New Jersey Medicaid program. PATIENTS: The study included New Jersey Medicaid enrollees 35 years of age or older. The 11,855 case patients were newly started on a hypoglycemic agent (oral agent or insulin) between 1981 and 1990. The 11,855 controls were selected randomly from among other Medicaid enrollees. MEASUREMENTS AND MAIN RESULTS: The frequency of initiation of hypoglycemic therapy was increased for users of virtually all antihypertensive agents relative to nonusers after adjustment for age, gender, race, nursing home residency, number of days hospitalized, total number of prescriptions, and selected medication exposures. The estimated relative risk for initiation of hypoglycemic therapy was 1.40 for patients receiving thiazide diuretics (95% CI, 1.26 to 1.58) and ranged from 1.56 to 1.77 for patients receiving other antihypertensive medications, depending on the medication category. A higher risk was associated with multiple-agent regimens, whether they excluded a thiazide diuretic (odds ratio, 1.76; CI, 1.49 to 2.07) or included one (odds ratio, 1.93; CI, 1.75 to 2.13). When the analysis was restricted to users of antihypertensive agents (n = 8005), the risk associated with other single-agent antihypertensive regimens was not significantly different from that associated with thiazide diuretics. However, patients receiving multiple-agent regimens continued to be at increased risk for hyperglycemia requiring hypoglycemic therapy relative to those who used thiazide diuretic therapy alone. CONCLUSION: The association between antihypertensive therapy and the initiation of treatment for diabetes mellitus is more closely related to the intensity of therapy than to the individual agent used. Our data do not support the hypothesis that thiazide diuretics are more strongly associated with the initiation of hypoglycemic therapy than are other antihypertensive agents.