Thiazide diuretics have been the cornerstone in the pharmacological treatment of hypertension for more than 5 decades. Hydrochlorothiazide and chlorthalidone have been the 2 most commonly used diuretics in major clinical trials and are considered interchangeable. Nonetheless, hydrochlorothiazide has been much more widely prescribed than chlorthalidone, especially since nearly all available combinations with other antihypertensive drugs contain hydrochlorothiazide. However, whereas chlorthalidone at low doses has been shown repeatedly to reduce cardiovascular morbidity and mortality, such low doses of hydrochlorothiazide have never been shown to do this. Moreover, in direct comparison, chlorothalidone has a more sustained antihypertensive effect than hydrochlorothiazide, probably due to its very long half-life. These beneficial effects on blood pressure and cardiovascular events make chlorthalidone a tenable choice for the treatment of hypertension.