Verapamil benefits patients with angina pectoris during exercise. The mechanism underlying this effect is controversial. A direct oxygen-sparing effect on ischemic myocardium has been proposed, but previous studies seeking to demonstrate this effect have been inconclusive because of inadequate control of systemic hemodynamics. This study has assessed the direct effects of verapamil on regional myocardial contraction during graded coronary flow reductions while blood pressure and heart rate were held constant. Verapamil caused a decrease in regional contraction at normal levels of coronary flow, a finding consistent with a negative inotropic effect. At lower coronary flows, however, ischemic dysfunction was similar in the presence and absence of verapamil. These findings fail to support the concept that verapamil either selectively depresses ischemic myocardium or enhances myocardial function during ischemia. Thus, these direct mechanisms would seem unlikely causes of the observed beneficial effect during exercise in patients with coronary artery disease.