Central nervous system (CNS) involvement occurred in 289 of 1332 patients (22%) with posttransplant non-Hodgkins lymphomas. The average time of appearance was 33 months (range 3 weeks to 248.5 months) posttransplantation. Lesions were confined to the CNS in 159 patients (55%), while 130 (45%) had involvement of other organs. Lesions involved the brain in 254 patients (88%), the brain and spinal cord in 5 (2%), the spinal cord in 2 (1%), unspecified locations in the CNS in 13 (4%), the meninges in 8 (3%), and the cerebrospinal fluid (CSF) in 7 (2%). All patients whose only involvement of the CNS was of the meninges or CSF had lymphomas involving multiple organs. Many tumors (48%) appeared within one year after transplantation. Brain lesions were frequently multicentric in distribution. Ninety-one (31%) of the 289 patients had no treatment and died, 70 (77%) of their malignancies and 21 (23%) from other causes. Of 198 patients who received treatment 124 (63%) died of their malignancies; 40 (20%) died of other causes, including 17 patients who had had complete remissions following treatment; 22 (11%) are currently alive and in complete remission; and 12 (6%) are alive and still undergoing therapy. The treatment of choice is local radiotherapy to the brain, which either alone (18 patients) or in combination with other modalities (14 patients) caused 32 of the 39 (82%) complete remissions. Ten of 30 patients with disease localized to the CNS survived more than 5 years, including 6 who survived more than 10 years. CNS lymphomas should be suspected whenever a transplant patient has neurologic symptoms however minor, and prompt work-up is essential to eliminate other possible causes. The dismal prognosis can be improved only by early diagnosis and prompt therapy.