In patients with uncomplicated mild to moderate hypertension, studies employing a double-blind randomized cross-over factorial design have been used to obtain more precise estimates of the hypotensive and biochemical effects of individual antihypertensive drugs and of their interactions when used in combination. Order and carry-over effects have been controlled. In studies with beta-blockers and diuretics, the hypotensive effects of the individual drugs have been confirmed and in combination their effects are additive. With the angiotensin-converting enzyme inhibitor, enalapril (20 mg daily) the hypotensive effect was additive with that of a diuretic, hydrochlorothiazide (50 mg daily). When enalapril was combined with the beta-blocker atenolol (50 mg daily) there was little additional hypotensive effect, despite similar hypotensive effects of the individual agents separately. The mechanism of this attenuated effect is unclear. The design is suitable for evaluation of other antihypertensive combinations.