Three cases of hypoxic-ischemic leukoencephalopathy were studied. In two patients, the neurologic disorder followed drug overdosage; in the third, the apparent precipitating event was a postoperative myocardial infarction complicated by circulatory insufficiency. All patients were deeply unresponsive, with varying reflex patterns. In all three cases, the brain showed extensive symmetrical necrotic lesions of the central white matter, with minimal damage to gray matter structures. The lesions in case 3 showed, in addition, vascular necrosis and ring hemorrhages. Common to all cases was a prolonged period of hypoxemia, hypotension, and elevated venous pressure. Acidosis occurred in two. These observations and analysis of previous reports of similar cases suggest that leukoencephalopathy tends to occur when the hypoxemia is prolonged and is associated with periods of hypotension and metabolic imbalance.