Even though hydrochlorothiazide (HCTZ) and chlorthalidone are frequently considered interchangeable antihypertensive agents, they appear to differ both in their blood pressure lowering efficacy and in their effects on the lipid profile and on serum potassium, uric acid and glucose levels. More importantly, in randomized controlled trials, chlorthalidone was equally or more effective than other antihypertensive agents in cardiovascular risk reduction whereas treatment with HCTZ yielded conflicting results. Although there are no randomized trials comparing the effects of these two agents on cardiovascular events, retrospective data from the Multiple Risk Factor Intervention Trial suggest that chlorthalidone might reduce cardiovascular morbidity more than HCTZ. However, current guidelines do not consistently recommend one or the other and it remains to be established which one is the diuretic of choice.