Myocardial apoptosis has previously been observed in human acute myocardial infarcts. We examined the time of appearance and extent of apoptosis in human acute myocardial infarcts, and compared these with necrotic cell death. Because nuclear internucleosomal DNA fragmentation is a hallmark of apoptosis, autopsied tissue from cases of acute myocardial infarct of varying histological ages was subjected to two tests that identify such fragmentation: in situ end-labeling (ISEL) and DNA electrophoresis on agarose gels. Both tests showed widespread apoptosis in infarcts only a few hours in age before the appearance of coagulative necrosis. No apoptosis was detected in normal myocardium. ISEL in recent infarcts was visible primarily in myocytes containing contraction bands, which occur predominantly in regions of reperfused myocardium. During the next 1 to 2 days, ISEL remained extensive but increasingly appeared in cells with morphological features of coagulative necrosis, representative of nonreperfused myocardium. In older infarcts, the incidence of apoptosis declined in myocytes, but increased in invading inflammatory cells. These data suggest that apoptosis is the early and predominant form of cell death in infarcted human myocardium, and that its appearance is accelerated in reperfused myocardium. Therapies directed at early rescue of apoptotic myocytes may, therefore, prove valuable.