Rabbit hearts perfused under hypoxic conditions underwent progressive subcellular damage, which becomes irreversible by one hour. During the first 20 minutes of perfusion, minor dilation of mitochondria and condensation of nuclear chromatin were the only salient features of cell injury. By 40 minutes moderate mitochondrial swelling was evident in hypoxic myocytes. Moreover, an increase in degenerating mitochondria and autophagic vacuoles was apparent. Reperfusion after either 20 or 40 minutes of hypoxia restored contractility, and injured myocytes underwent a cellular repair process that involved a dramatic increase in lysosomal autoplagy. One hour of hypoxia yielded irreversibly injured myocytes. Upon reoxygenation, some of these cells displayed typical changes of necrosis, but others apparently underwent an abortive repair process involving the formation of large, probably nonfunctional lysosomes. These observations suggest that lysosomal autophagy is important in the efforts at repair that cardiac cells initiate during and after hypoxia.