Cryptococcus neoformans infections in patients with AIDS are often incurable, despite aggressive antifungal therapy. Combination regimens with additive or synergistic drugs could provide additional options for treating cryptococcal meningitis. We evaluated the efficacy of combination therapies using L-743,872, a pneumocandin antifungal drug, and amphotericin B or fluconazole against 18 strains of C. neoformans, including 11 C. neoformans var. neoformans, 3 C. neoformans var. gattii, and 4 fluconazole-resistant isolates. The combination of subinhibitory concentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C. neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Clinical and Laboratory Standards method), quantitative CFU, and tetrazolium salt reduction assays. Similarly, the addition of subinhibitory concentrations of L-743,872 to fluconazole enhanced fluconazole activity, but the effect was less dramatic than for the pneumocandin-amphotericin B combination. A marked synergism was observed in all combinations of amphotericin B and L-743, 872 (fractional inhibitory concentration index [FIC] of < or = 0.5). Fluconazole-resistant strains showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates. Combinations of pneumocandin with fluconazole revealed different activities for the various strains, including synergism (FIC < 1.0), additivity (FIC = 1.0), and autonomy (FIC between 1.0 and 2.0). Combination studies with fluconazole and L-743,872 showed additive and autonomous activities against fluconazole-resistant isolates. No antagonistic interactions (FIC < 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole. The results of this study suggest that L-743,872 can enhance the efficacy of fluconazole or amphotericin B in vitro and indicate a potential role for L-743,872 in combination therapy against C. neoformans.