Reperfusion following myocardial ischemia has been postulated to cause myocardial edema resulting in increasing interstitial pressure and retardation of the microcirculation. If ischemia then is repeated, the additional insult results in increasing edema and possible infarction. In order to test this hypothesis, 15 pigs were placed on cardiopulmonary bypass with coronary perfusion maintained at 100 mm. Hg by a separate pump through the clamped aortic root. Coronary flow and vascular resistance were recorded. Distribution of coronary blood flow was monitored by injection of radioactively labeled microspheres (15 mu). Myocardial extravascular water was measured by simultaneously determining myocardial intravascular water with radioactive iodinated serum albumin (RISA) and total myocardial water with tritiated water (THO). Three 30 minute periods of myocardial ischemia and 5 minutes of coronary perfusion produced (1) a loss of the reactive hyperemic response to ischemia (coronary vascular resistance increased--from 0.295 +/- 0.024, control, to 0.366 +/- 0.042, after anoxia--rather than decreasing with reactive hyperemia induced vasodilatation); (2) a significant maldistribution of coronary flow away from the endocardium (endocardial: epicardial perfusion ratio 1.10 +/- 0.05, control, to 0.69 +/- 0.08, following ischemia, p less than 0.05); and (3) significant myocardial edema. Myocardial extravascular water rose from 46.4 +/- 1.7 ml. per 100 Gm., control, to 52.6 +/- 2.0 ml. per 100 Gm., after ischemia (p less than 0.05), whereas intravascular myocardial volume did not change significantly. Both light and electron microscopic examination of the postischemic myocardium shows interstitial and intracellular edema with typical ischemic changes at a cellular and subcellular level. The significant increase in myocardial extravascular water content associated with this injury supports the concept that myocardial reperfusion plays a role in its development.