The risk of neurotoxicity was evaluated in eight consecutive patients with non-acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma who had survived disease free for more than 1 year after completion of treatment with osmotic opening of the blood-brain barrier and chemotherapy (methotrexate, cytoxan, procarbazine, and decadron). Trends in neuropsychological assessment results between baseline and follow-up (1 to 7 years) were analyzed for all eight nonradiated survivors. This serial assessment design addressed the specific issue of neurotoxic risk potential of treatment, when confounding factors of tumor persistence/recurrence and cranial irradiation were ruled out. Follow-up results of an extensive battery of tests to assess higher cortical function provided evidence of the safety of chemotherapy protocol with the blood-brain barrier disruption. These findings stand in contrast to well-known cognitive risks associated with cranial radiotherapy. Long-term follow-up suggests that chemotherapy can be given in conjunction with osmotic opening of the blood-brain barrier in nonradiated patients without cognitive manifestations of neurotoxicity.