A nonrandomized trial was undertaken to evaluate the combination of didanosine and interferon-α (IFN-α) in human immunodeficiency virus (HIV)-infected patients. Thirty-six volunteers with >200 × 106 CD4 cellslL received didanosine (one 100-,250-, or 375-mg sachet twice daily) for at least 6 weeks, following which IFN-α (1, 5, 10, or 15 MU/day) was begun. Didanosine (one 375-mg sachet twice daily) was substituted for zidovudine in 14 additional patients who had received IFN-α and zidovudine for 7-45 months. Thirty-five patients completed the 34-week study. Clinical or chemical pancreatitis was the most common (6 patients) dose-limiting toxicity. CD4 cell counts increased with didanosine but declined following the addition of IFN-a; CD4 cell percents tended to increase and remain elevated. Thus, combination therapy with didanosine and IFN-α can be safely administered to patients with HIV infection. The clinical benefit of this combination therapy will require further evaluation.