The cases of 283 small cell lung cancer patients who received treatment with combination chemotherapy with or without prophylactic cranial irradiation (PCI) were reviewed to determine the incidence of leukoencephalopathy. The overall incidence was 10%. Of all patients receiving PCI, 17% developed neurotoxicity, and of those receiving PCI and surviving greater than or equal to 1.5 years, 37% suffered neurologic sequelae. In those receiving PCI but surviving less than 1.5 years, the incidence of neurotoxicity was 4%. The mean time interval between the end of PCI and the onset of neurotoxicity was 17 months (range 2-63 months). The PCI dose ranged from 2600-3600 cGy. None of the patients not receiving PCI developed neurotoxicity. The incidence of neurotoxicity in long-term survivors (greater than or equal to 1.5 years) with respect to PCI dose was less than or equal to 3000 cGy (25%), 3200 cGy (56%), 3600 cGy (36%). Almost all of the patients getting PCI also received lomustine, an agent associated with DNA repair inhibition and synergism with DNA damaging agents such as ionizing radiation or alkylating agents. Under the conditions of our study, PCI was associated with an unacceptable risk of neurotoxicity. Until further information is forthcoming, one should proceed with caution when using PCI in conjunction with lomustine.