Germfree transgenic epsilon 26 (Tgepsilon26) mice, which express the full-length human CD3epsilon gene, have combined defects in natural killer (NK) cells and T cells were found to be extremely susceptible to oroesophageal (palate, tongue, esophagus) and gastric (cardia-antrum section) candidiasis. The gnotobiotic Tgepsilon26 mice die, apparently from severe oroesophageal candidiasis, within 2-4 weeks after their alimentary tracts are colonized with Candida albicans. The Tgepsilon26 mice manifest resistance to acute systemic candidiasis (intravenous injection) and to systemic candidiasis of endogenous origin for the first 2 weeks after their alimentary tracts are colonized with C. albicans. Granulocyte depletion data suggest that granulocytes, in the absence of functional NK cells and T cells, can protect Tgepsilon26 mice from acute systemic candidiasis and from systemic candidiasis of endogenous origin, for at least 14 days after alimentary tract colonization. Granulocytes and macrophages, in the absence of NK cells and T cells, are unable to protect Tgepsilon26 mice from lethal oroesophageal candidiasis and systemic candidiasis of endogenous origin which was evident in moribund Tgepsilon26 mice 2-4 weeks after colonization. Thus, non-T cells (i.e., NK cells) and T cells play important roles in resistance to oroesophageal and systemic (acute and of endogenous origin) candidiasis.