We conducted a phase 2, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)-γ1b in patients with acquired immunodeficiency syndrome and acute cryptococcal meningitis. Patients received 100 or 200 μg of rIFN-γ1b or placebo, thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin B, with or without flucytosine, followed by therapy with fluconazole. End points included conversion of cerebrospinal fluid fungal cultures from positive to negative at 2 weeks, resolution of symptoms, and survival. Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN-γ1b (100 μg) recipients, and 32% of rIFN-γ1b (200 μg) recipients. There was a trend toward improved combined mycologic and clinical success in rIFN-γ1b recipients (26% vs. 8%; P = .078). Therapy with rIFN-γ1b was well tolerated, and there was no apparent influence on serial CD4 cell counts and human immunodeficiency virus load measurements. Adjunctive therapy with rIFN-γ1b holds promise for patients with acute cryptococcal meningitis and warrants further study.