The safety and tolerability of antihypertensive therapies are an important clinical concern, because the demonstrated benefits of successful blood pressure-lowering depend on long-term compliance with pharmacologic treatments. Thiazide diuretics and beta blockers have been specifically recommended as preferred initial drug therapy by the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V), unless their use is contraindicated by concomitant disease, there is intolerance to these agents, or there is a specific indication for another drug class. These recommendations are a result of the lengthy clinical experience with these drugs and the results of long-term clinical trials that have demonstrated significant reductions in cardiovascular morbidity and mortality. However, data from these same clinical studies have also shown that diuretics (and beta blockers) can cause abnormalities in carbohydrate, electrolyte, and lipid metabolism and also may influence quality of life. The safety of diuretics was evaluated with regard to effects on carbohydrate, electrolyte, and lipid metabolism by seeking references from a MEDLINE search of documents published from 1966 to 1994 based on the search terms "hypertension," "human," and "hydrochlorothiazide" (HCTZ) dosed in a range of 12.5-25 mg daily. Two long-term clinical trials using low-dose (12.5-15 mg/day) chlorthalidone-the Systolic Hypertension in the Elderly Program (SHEP) and the Treatment of Mild Hypertension Study (TOMHS)-were also included. During the course of treatment with HCTZ in these studies, serum potassium was reduced and uric acid was increased in a dose-dependent manner. Although low doses of HCTZ elevated serum glucose, cholesterol, and triglycerides, the magnitude of effect was small in most cases and was probably of no clinical significance. Other laboratory parameters were not adversely affected, and subjective reporting of clinical adverse events was generally lower with low-dose HCTZ than with placebo or standard HCTZ dosing. The literature on the effects of low-dose diuretic therapy on quality of life is not large, although the results from the SHEP and TOMHS studies support the concept that diuretics either do not interfere with, or may actually improve, quality of life in hypertensive patients. Low-dose thiazide treatment is a well-tolerated, excellent first-line choice for hypertensive patients, especially older patients. However, diuretics should probably be avoided, whenever possible, in patients with preexisting diabetes, gout, and in men with erectile dysfunction.