We examined the importance of a long plasma half-life (t1/2) on the antianginal effects of beta-blockade by comparing equivalent doses of once-daily atenolol 100 mg (t1/2 6-8 h) and betaxolol 20 mg (t1/2 20-22 h) in a double-blind placebo-controlled cross-over study of 20 patients with stable angina pectoris. At 20 h postdose, heart rate (HR) was lower with betaxolol than with atenolol whereas blood pressure (BP) was equally reduced by both drugs. Twenty-four-hour ambulatory HR recording demonstrated that this difference existed for the last 6 h of the dosage cycle. During treadmill exercise, HR remained lower with betaxolol than with atenolol and exercise time was significantly prolonged only by betaxolol. With placebo, radionuclide ventriculography demonstrated that left ventricular ejection fraction (LVEF) decreased during exercise. Betaxolol, but not atenolol, significantly attenuated the exercise-induced decrease in EF. Thus, the long plasma t1/2 of betaxolol is associated with a reduction in exercise-induced ischemia when tested toward the end of the 24-h dosage cycle. Plasma t1/2 therefore is of clinical relevance to the antianginal, but not antihypertensive, actions of beta-blockers.