The role of fluconazole in the treatment of many forms of focal mycoses remains unclear. We studied the effectiveness of three different oral doses of fluconazole in three murine models of Candida albicans peritonitis leading to intra-abdominal abscess formation. During monomicrobial Candida infection, fluconazole decreased mortality and the number of C. albicans cultured per abscess; prolonged treatment also eliminated Escherichia coli translocation. In mixed C. albicans/E. coli/Bacteroides fragilis infection, prolonged treatment with higher doses of fluconazole decreased mortality, the number of abscesses formed, and the number of C. albicans per abscess. In animals with a similar polymicrobial infection but with concurrent cefoxitin treatment, fluconazole decreased mortality and the number of C. albicans per abscess; in addition, prolonged treatment reduced the number of abscesses. Amphotericin B gave similar results in all three models. These data indicate that the clinical use of fluconazole in peritonitis should be investigated.