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For nearly 30 years clinicians have assumed that diuretic therapy, per se, even in the absence of clinical hypokalemia, can cause false-positive exercise ST-segment responses. The precept has stubbornly persisted in the literature and in the day-to-day interpretation of exercise tests in clinical settings. The assumption probably originated with very early studies of patients on diuretics, in which other causes of false-positive tests were not excluded. This study was undertaken to show that diuretic therapy alone is not sufficient to cause ST depression. Twenty healthy male volunteers, aged 18 to 35, with normal history and physical examinations, echocardiograms, electrocardiograms, serum electrolytes, renal function tests and exercise tests, took 50 mg of hydrochlorothiazide daily for four weeks. Exercise tests, serum electrolytes, and renal function tests were repeated at Weeks 2 and 4. The administration of the diuretic resulted in a statistically significant reduction in serum potassium (from 4.37 +/- 0.37 to 3.96 +/- 0.28, and 3.94 +/- 0.31 mEq/l at 2 and 4 weeks, respectively). There were no abnormal ST-segment shifts on any of the exercise tests. It is concluded that exercise-induced ST-segment shifts in otherwise healthy young male normokalemic subjects who are taking diuretics should not be ascribed to a false-positive response to diuretics.