We compared amphotericin B therapy for cryptococcal meningitis with a newer regimen containing both amphotericin B and flucytosine. In 50 patients with 51 courses of therapy adherent to the protocol, 27 courses were with amphotericin B and 24 with the combination. Even though the combination regimen was given for only six weeks and amphotericin B for 10 weeks, the combination cured or improved more patients (16 vs. 11), produced fewer failures or relapses (three vs. 11), more rapid sterilization of the cerebrospinal fluid (P<0.001) and less nephrotoxicity (P<0.05) than did amphotericin B alone. The number of deaths was the same (five) with each regimen. Adverse reactions to flucytosine occurred in 11 of 34 patients but were not life threatening. We conclude that combined flucytosine-amphoericin B therapy is the regimen of choice in cryptococcal meningitis. (N Engl J Med 301:126–131, 1979) CRYPTOCOCCAL meningitis was a uniformly fatal disease before the introduction of amphotericin B.1 Although cures are obtained in 53 to 58 per cent of patients,2,3 amphotericin B therapy requires prolonged treatment and toxicity is substantial. Flucytosine can also cure this infection, but secondary drug resistance and a low proportion of cures make this drug undesirable as a single agent.4 In vitro5 and in vivo6 evidence that amphotericin B and flucytosine were at least additive in their effects against cryptococcosis prompted clinical trials of the combination. In a prospective, though uncontrolled, trial7 of combination therapy in 15 patients with cryptococcal meningitis,. © 1979, Massachusetts Medical Society. All rights reserved.