Primary central nervous system (CNS) lymphoma, an otherwise rare pediatric tumor, has been reported with increasing frequency in children with acquired immune deficiency syndrome (AIDS). With current therapy, the outcome of this disease is invariably fatal. The authors present a case of primary CNS lymphoma in a 3.5-year-old girl with AIDS who received treatment with total brain irradiation. After treatment, the patient's mental status improved, the seizures resolved, and she had no further progression of her neurologic symptoms until she died of pneumonia 6 months later. The autopsy revealed a necrotic mass at the site of the original tumor. The brain stem and spinal cord, unirradiated, contained lymphomatous lesions. The patient had extensive fibrinoid necrosis and leukoencephalopathy that were consistent with radiation-induced CNS damage. Coexisting AIDS encephalopathy also contributed to the patient's CNS injury. Effective palliation of CNS lymphoma in children with AIDS may be obtained with cranial irradiation. Pediatric AIDS patients may show more severe tissue effects from irradiation than unaffected children.