Two initially healthy infants developed acute encephalopathic illnesses characterized by stupor, seizures, cerebrospinal fluid (CSF) erythrocytic and monocytic pleocytosis, increased CSF protein, and decreased CSF glucose and progression to chronic decerebration. In one case, herpes simplex virus was recovered from cutaneous lesions. The initial computed tomography (CT) scan revealed widespread subcortical increased attenuation with further increase after contrast medium injection and patchy areas of decreased attenuation in the deep cerebral white matter. Subsequent CT scans demonstrated progressive cortical calcifications and persistence of low attenuation areas. Autopsy revealed multiple cystic encephalomalacia. The second infant had similar clinical. CSF, and CT findings but remains in a chronic decerebrate state at 14 months of age. The CT abnormalities seen in these patients have not been encountered in any of 13 other infants with the clinical diagnosis of meningitis or encephalitis. Multiple cystic encephalomalacia of infancy is a rare condition with a uniformly bleak prognosis. Computed tomography may prove useful in the early diagnosis, thereby aiding clinicians in counseling and in the acute and long-term management of patients with this lesion.