This phase 1 trial was conducted to evaluate the safety and tolerance of didanosine (ddI) in subjects with AIDS or AIDS-related complex (ARC) who previously had demonstrated hematologic intolerance of zidovudine. Thirty subjects, 21 with AIDS and nine with ARC, were enrolled. Initially, didanosine was administered orally twice daily for a total daily dose of either 750 mg or 1,500 mg. Subsequently, the dosage for those receiving 1,500 mg/d was reduced to a maximum of 750 mg/d (375 mg twice daily) when data from this and other phase 1 studies showed that the dosage of 1,500 mg/d (750 mg twice daily) was associated with an unacceptable risk of developing neuropathy. The subjects were studied for 46 weeks (mean time; range, 7–122 weeks). The dose-limiting toxic effect observed was peripheral neuropathy, which occurred in eight patients. Other significant toxic effects included pancreatitis in three patients and xerostomia in eleven. In general, didanosine was well tolerated from a hematologic standpoint by the majority of patients during prolonged administration.