Starting in 1988, 72 patients with advanced human immunodeficiency virus (HIV) infection were enrolled in a phase I study of didanosine at the National Cancer Institute. Beginning in 1992, patients with decreases in CD4 cell counts could switch to a combination of zidovudine and didanosine. The estimated median survival for all patients was 28 months (95% confidence interval, 23-46). However, for patients whose entry CD4 cell counts were 100-300/mm3, the estimated 4-year survival was 80%. Baseline CD4 and CD8 cell counts, hemoglobin, lymphocytes, sedimentation rates, diagnosis of AIDS, and fever were significant predictors of overall survival. Principal toxicities were pancreatitis and peripheral neuropathy; no new toxicities were seen with extended didanosine treatment that had not been observed in shorter-term studies. This 5-year follow-up shows that didanosine can be tolerated for > 4 years in some patients with advanced HIV infection and may have particular long-term utility in patients with moderately advanced immunosuppression.