An assault on old friends: thiazide diuretics under siege. The adverse biochemical effects of thiazide use are of uncertain clinical significance. Thiazides raise LDL cholesterol only slightly in long-term studies and do not decrease HDL cholesterol. The evidence linking thiazide-induced hypokalemia with arrhythmias and sudden death is tenuous at best. Thiazide diuretics cause glucose intolerance, but no strong evidence has been advanced to suggest that this is dangerous. Because these effects are probably related to hypokalemia, a randomized trial comparing the effects of thiazides with thiazides plus a potassium-sparing diuretic on LDL cholesterol, ectopy on 48 hour ambulatory cardiac monitoring, fasting glucose and insulin, and post-glucose tolerance glucose and insulin would be of interest. The most compelling reason for continuing to use thiazides is that they have been shown in long-term randomized studies to reduce cardiovascular risk. Beta-blockers are the only other class of anti-hypertensive agent for which this claim can be made. The importance of long-term clinical trials in assessing the efficacy and toxicity of therapeutic agents is illustrated by the study that found clofibrate reduced cholesterol levels and coronary disease but increased total mortality. This finding remained undetected until a large randomized long-term trial was completed. Thiazide diuretics have not reduced the rate of coronary disease to the degree expected from epidemiologic studies, but the short length of the randomized trials may be responsible. It is not clear that other anti-hypertensive agents will be superior. Thiazides are less expensive than other anti-hypertensive agents being touted as metabolically safer; the cost issue is not a trivial matter. 