Three patients developed the sudden onset of total blindness several months after treatment with oral CCNU and low-dose whole-brain radiation. The anterior visual system was included in the radiation field in all patients. Radiotherapy was given for a frontal-lobe glioblastoma multiforme, for central nervous system prophylaxis in a patient with oat cell carcinoma of the lung, and for a parietal-lobe glioblastoma multiforme. None of the neoplasms involved the anterior visual system. The radiation dose ranged from 3000 to 4650 rad and the oral CCNU dosage from 300 mg to 1050 mg. Patients 1 and 2 also received other chemotherapeutic agents. Patient 3 who was treated only with oral CCNU and cranial irradiation died. At autopsy the brain showed a widely infiltrating residual high-grade glioma as well as patchy coagulative necrosis with swollen axons and dystrophic calcifications. The optic chiasm showed severe demyelination, axonal loss, and hyalinized vessels. Synergism between oral CCNU and radiation may account for the blindness produced.