OBJECTIVE To evaluate safety, tolerance, and potential efficacy of interferon-alpha and zidovudine combination therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). METHODS Open, phase-I study with randomization between two preparations of interferon-alpha. METHODS Outpatient clinic of a cancer research center. METHODS Forty-three patients with Kaposi sarcoma associated with AIDS. METHODS Patients were treated with interferon-alpha, 4.5, 9, or 18 million U/d, and zidovudine, 100 or 200 mg orally every 4 hours. RESULTS Neutropenia was the major dose-limiting toxicity. Fatigue, liver enzyme elevation, anemia, and thrombocytopenia were dose-limiting in some patients. Maximum tolerated dosages for interferon-alpha 2a with zidovudine, respectively, were 4.5 million U/d with 200 mg every 4 hours or 18 million U/d with 100 mg every 4 hours. An interferon-alpha n1 [corrected] dosage of 9 million U/d with zidovudine dosages of either 100 or 200 mg every 4 hours induced dose-limiting toxicity in most patients. Of 37 evaluable patients, 17 (46%; 95% CI, 30% to 62%) showed complete or partial tumor regression. Antitumor effects occurred more frequently in patients with baseline CD4 counts above 200 x 10(6) cells/L (65%) than in patients with lower baseline counts (30%, P = 0.05). Effects on CD4 cells were related to both initial CD4 count and interferon dose. Increased skin test reactivity and decreased serum human immunodeficiency virus (HIV) p24 antigen and virus recovery from blood cells were seen. CONCLUSIONS Combined therapy with interferon-alpha and zidovudine can be safely administered to patients with AIDS and Kaposi sarcoma. The observed effects on tumor growth, HIV replication, and immune function support further studies of the combination in patients at various stages of HIV infection.