The effect of antihypertensive therapy with guanabenz or hydrochlorothiazide (HCTZ) on the secretion of growth hormone, prolactin, insulin, and glucagon was evaluated in double-blind fashion in 45 patients. Fifteen patients were treated with HCTZ, 50 mg twice daily, and 30 patients were treated with twice-daily dosages of guanabenz ranging from 4 to 32 mg. Blood samples for hormone analysis were collected during maintenance therapy when blood pressure was controlled as well as 1 week after the withdrawal of the antihypertensive medications. Serum levels of growth hormone and prolactin were within the normal ranges and were unchanged during treatment with HCTZ or guanabenz at any dose level. Interpatient variability in insulin levels was high, although within-subject insulin levels generally were consistent. No treatment effects were seen for insulin levels among guanabenz- or HCTZ-treated patients. Glucagon levels generally were above the expected range for fasting patients and were lower in patients receiving 4 or 8 mg of guanabenz twice daily than in those receiving 16 mg twice daily (p less than 0.05) and in those treated with HCTZ (p less than 0.01). However, analysis of paired data revealed no changes in glucagon levels upon withdrawal of guanabenz, whereas glucagon levels were higher during HCTZ treatment than after drug withdrawal (p = 0.012). Since guanabenz treatment did not affect the secretion of pancreatic or pituitary hormones, it may be preferable to other centrally acting agents and thiazide diuretics for hypertensive patients who are elderly, overweight, or diabetic.