The present study was undertaken to determine whether diminished coronary blood flow without abrupt reperfusion results in myocardial cell swelling and, if so, whether the increment in tissue water is related to an increase in coronary vascular resistance. In 19 anesthetized open-chest dogs on right heart bypass with controlled coronary perfusion a decrease in coronary flow resulted in an increase in intracellular water and a progressive increase in coronary resistance. In 15 additional dogs, 180 min of ischemia produced by partially occluding the circumflex coronary artery resulted in significant increases in myocardial water content and progressive decreases in regional myocardial blood flow (microsphere technique). A significant correlation was found between the progressive decreases in myocardial flow and the increases in myocardial water (r = -0.82, P less than 0.001). In five experiments, hypertonic mannitol prevented water accumulation and progressive decreases in blood flow in the ischemic tissue. Thus myocardial ischemia produced by a decrease in antegrade coronary perfusion results in myocardial cell swelling and an associated progressive perfusion deficit.