Mice depleted of T-lymphocytes by thymectomy and irradiation (TXB) and immunologically competent mice were compared for gross and histological pathology as well as immune responses after cutaneous and/or intravenous challenge with Candida albicans. In response to a first cutaneous inoculation with viable Candida, TXB, sham-operated (SXB), and unmanipulated (normal) mice, all developed lesions of comparable size, duration, and histopathology. When challenged a second time cutaneously, normal and SXB mice developed lesions which were greatly increased in size when compared with those produced by a first cutaneous infection, whereas TXB mice developed lesions comparable in size to those initiated by the first infection. Histologically, the first and second lesions in all animals were acute abscesses predominantly comprised of polymorphonuclear leukocytes. The larger second lesions in SXB and normal mice were accompanied by detectable circulating antibody and by delayed hypersensitivity. Neither circulating antibody nor delayed hypersensitivity were stimulated in the TXB mice. When challenged intravenously, all previously uninfected mice, regardless of T-cell status, were equally susceptible to C. albicans. Contrary to SXB or normal mice, however, TXB mice which had been infected cutaneously were not more resistant to a subsequent intravenous challenge as judged by 6-week survival. The results suggest that T-cells do not play a significant role in innate resistance of mice to systemic candidiasis, but that such cells are important in the development of acquired resistance.Candida albicans (Robin) Berkhout is a fungus which does not usually invade the normal host, although it is a member of the normal human microbial flora. The mechanism by which healthy individuals resist invasion is unclear, but it is generally believed that cell-mediated immunity, and thus the T-lymphocyte, is an important factor in acquired resistance. The latter statement is based primarily on clinical evidence, in that individuals with immunodeficiency diseases (3,18,22,32,35) or with diseases for which the treatment itself is immunosuppressive (1, 17, 20, 24, 28, 37) are particularly susceptible. Experimental evidence to corroborate the clinical evidence is somewhat meager.Recently, however, a natural model of immunological modification, viz., the nude or athymic mouse, has been used to investigate innate resistance to C. albicans. Cutler (10) inoculated nude mice with large doses of C. albicans intravenously and observed that such mice were more t Present address: Mt. Sinai Hospital, Department of Microbiology, New York, NY 10029.