This study details the type, frequency, clinical presentation, and etiologic associations of acquired brain lesions in 40 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Detailed postmortem neuropathologic examinations showed that 55% of the infants were free of acquired brain lesions. However, the other 45% had combinations of hypoxic-ischemic lesions and intracranial hemorrhage. Central nervous system perfusion and glucose-oxygen delivery appeared to be important factors in the occurrence of hypoxic-ischemic lesions or intracranial hemorrhage, whereas acidosis and hypercarbia were not. Cerebral necrosis may be a predisposing factor for a major intracranial hemorrhage. A duration of cardiopulmonary bypass with hypothermic total circulatory arrest longer than 40 minutes was associated with a higher incidence of acquired neuropathology. These results indicate that the majority of infants with hypoplastic left heart syndrome are free of acquired neuropathology and suggest practical ways to reduce the risks in the others.