The comparative activities of two preparations of amphotericin B against Coccidioides immitis were investigated. These preparations were a deoxycholate suspension (conventional amphotericin B) and a lipid-based formulation, amphotericin B lipid complex (ABLC). In-vitro susceptibility testing demonstrated that the MICs of ABLC were ≤ 0·25 mg/L and of conventional amphotericin B were 0·5 mg/L for C. immitis. However, conventional amphotericin B was at least four-fold more fungicidal, with a minimum fungicidal concentration of 4·0 vs > 16 mg/L for ABLC. The therapeutic efficacies were tested in murine models of acute systemic coccidioidomycosis. Female CD-I mice were infected iv with C. immitis arthroconidia to establish high (> 50%) or low (< 50%) mortality models. Therapy with conventional amphotericin B or ABLC was given three times per week for two weeks starting three days post-infection. Controls received no therapy or drug-free diluent only. Survival was tallied up to 49 days post-infection and the fungal cfu counts in spleen, liver, and lungs of all survivors were determined. In the low mortality study all treated mice survived and all therapy regimens reduced infection in all organs. All mice given ABLC 6·6 or 13·2 mg/kg/dose and 80% given ABLC 16·5 mg/kg/dose, as well as 90% given conventional amphotericin B 0·66 mg/kg/dose were free of infection; all controls remained infected. In two high mortality studies, all mice given ABLC 0·66–20 mg/kg/dose or conventional amphotericin B 0·22 or 0·6 mg/kg/dose survived compared with 0·20% of controls. Thirty percent of uninfected mice given ABLC 20mg/kg/dose and 40% given conventional amphotericin B 2·0 mg/kg/dose died due to drug toxicity. Mice given ABLC or conventional amphotericin B had lower residual cfu counts of C. immitis in all organs than did controls. Sixty to one hundred per cent of mice given ABLC regimens ≥ 6·6 mg/kg/dose were cured, whereas all controls and 50·60% of mice receiving the highest non-toxic conventional amphotericin B regimen (0·66 mg/kg/dose) remained infected. At equal non-toxic amphotericin B doses, conventional amphotericin B was more effective than ABLC in reducing cfu in infected organs. Although conventional amphotericin B was about three-fold more active on a mg/kg basis, ABLC was ≥ 10-fold less toxic, and could be given at higher, curative doses. Thus, the therapeutic index of amphotericin B is improved when given as ABLC. ABLC should be further tested in other animal models and clinically.