We have documented visual and auditory neurotoxicity in 42 of 89 patients with transfusion-dependent anemia who were receiving iron chelation therapy with subcutaneous deferoxamine (DFO). Of the affected groups, 13 presented with visual loss or deafness or both, and ophthalmologic, audiologic, and visual evoked potential studies (VEPs) uncovered abnormalities in 29 more. Four patients with visual loss had optic neuropathy with a marked decrease in acuity and loss of color vision. These 4, and 16 other asymptomatic patients, had abnormal VEPs. When DFO was stopped, 3 of 4 with visual problems regained normal visual function but VEPs remained abnormal. Of the other 16 with abnormal VEPs, 9 became normal or improved and 7 did not change; on restarting DFO, the 9 became abnormal again. There were 22 abnormal audiograms that showed a high-frequency sensorineural deficit; 13 patients were symptomatic and 4 needed hearing aids. On stopping DFO, 9 became asymptomatic but 15 audiograms remained abnormal and 2 deteriorated further on restarting the drug. An analysis of the clinical data showed that members of the affected group were younger, had lower serum ferritin values, and were self-administering higher doses of DFO/kg body weight. Significantly lower doses of DFO were being taken by patients without abnormalities than by those with visual symptoms, abnormal audiograms, or prolonged VEPs (P less than 0.001, less than 0.006, and less than 0.04, respectively). The data implicate high-dose DFO as a central factor in the pathogenesis of the neurotoxicity. Our serial studies provide the basis for effective yet safe DFO administration for patients who require the agent.