In 2 randomised, prospective Eastern Co-operative Oncology Group trials, the frequency of central nervous system (CNS) involvement after chemotherapy in 347 adults with stage III and IV unfavourable-histology, non-Hodgkin's lymphoma was 8.4%. The frequency varied from 0% in diffuse mixed lymphoma to greater than 30% in lymphoblastic and diffuse-undifferentiated lymphoma. Of the 42% of patients who achieved complete remission after chemotherapy, CNS involvement developed in 5.4% during relapse, but in only 2.7% was the CNS the sole site of relapse. CNS lymphoma arose in 6.6% of 197 patients with diffuse histiocytic lymphoma, but in only 1 subject (1%) was the CNS the sole site of relapse. Therefore, CNS prophylaxis is not indicated for the common diffuse-histology subtypes of adult non-Hodgkin's lymphoma including diffuse-histiocytic, diffuse-mixed and diffuse poorly differentiated lymphocytic lymphoma. The relatively high frequency of CNS lymphoma in lymphoblastic and diffuse undifferentiated lymphoma justify further studies of CNS prophylaxis.