Germ-free C57BL/6 x 129 interferon-gamma knockout (IFN-gamma(-/-)) mice and their immunocompetent (+/-, +/+) counterparts were colonized with a pure culture of Candida albicans to assess their natural susceptibility to mucosal and systemic candidiasis of endogenous origin. Colonization with a pure culture of C. albicans was not lethal for adult or neonatal IFN-gamma(-/-) gnotobiotic mice over the 15-week study. The IFN-gamma(-/-) mice were more susceptible to gastric (cardia-antrum section), anorectal, and acute systemic (intravenous challenge) candidiasis than immunocompetent controls, and some IFN-gamma(-/-) mice developed intestinal adenomas after colonization with C. albicans. The enhanced susceptibility of IFN-gamma(-/-) mice, compared with immunocompetent controls, may be associated with a poor proliferative response of spleen cells to C. albicans antigens and a T helper 2 (IgG1) serum antibody response to C. albicans antigens. Thus, IFN-gamma is important for murine resistance to gastric, anorectal, and acute systemic candidiasis.