Mortality after intravenous challenge with 10(4) Cryptococcus neoformans demonstrated that doubly immunodeficient beige athymic (bg/bg nu/nu) mice were more susceptible to systemic cryptococcosis than either bg/bg or nu/nu mice. Infected bg/bg nu/nu mice also had a shortened lifespan compared with their bg/bg nu/+ littermates. Beige athymic (bg/bg nu/nu) but not bg/bg nu/+mice developed cryptococcal lesions in the skin, demonstrating that C. neoformans is dermatotropic in a T-cell-deficient host. Higher numbers of C. neoformans were isolated from the lungs and spleen of infected bg/bg nu/nu than bg/bg nu/+ mice as early as day 3 after challenge, indicating that in lymphoid-rich organs, T cells can alter the course of systemic cryptococcosis early in the infection. Despite extensive abscess formation in the brains of bg/bg nu/+ mice, dissemination and growth rate of C. neoformans in the brain was similar in both genotypes. The primary histopathological feature in tissues from bg/bg nu/nu mice infected with C. neoformans consisted of foci of encapsulated yeast cells with minimal to no inflammatory response. In contrast to bg/bg nu/nu mice, bg/bg nu/+ mice mounted a vigorous inflammatory response to C. neoformans that progressed from acute to chronic inflammation. Beige athymic mice are a new animal model that will be useful in clarifying the innate and acquired immune factors important in resistance to cryptococcosis.