Right ventricular failure during acute pressure overload has been attributed to ischemia which occurs when maximal coronary vasodilation is achieved so that further increases in myocardial blood flow cannot occur. To test the hypothesis that coronary vasodilator reserve is exhausted during acute right ventricular pressure overload, right and left ventricular myocardial blood flow was measured in 14 awake dogs during progressive pulmonary artery occlusion; coronary vasodilator reserve was tested by infusion of adenosine (4 μM/kg per min) before and during pulmonary artery occlusion. Right ventricular myocardial blood flow rose from 0.77 ± 0.09 ml/min per g (mean ± SEM) during control conditions to 1.69 ± 0.26 ml/min per g during moderate pulmonary artery occlusion (P < 0.01). With further pulmonary artery occlusion to cause increased right ventricular end-diastolic pressure and decreased aortic pressure, a selective decrease in myocardial blood flow to the right ventricular subendocardium was observed, and the right ventricular subendocardial-to-subepicardial blood flow ratio fell from 1.36 ± 0.14 to 0.77 ± 0.06 (P < 0.05). With restoration of mean aortic pressure to control levels, right ventricular systolic pressure increased, right ventricular end-diastolic pressure decreased, and the right ventricular subendocardial-to-subepicardial ratio increased to 1.36 ± 0.18 (P < 0.01). Adenosine infusion during pulmonary artery occlusion in five dogs caused an increase in mean right ventricular blood flow (1.11 ± 0.10 to 2.25 ± 0.30; P < 0.05). This increase was most marked in the outer layers but, nevertheless, was also significant in the subendocardium. These data indicate that acute severe right ventricular pressure overload may be associated with right ventricular subendocardial hypoperfusion, even when coronary vasodilator reserve is not exhausted.