A Cryptococcus neoformans infection in congenitally athymic (nude) mice and phenotypically normal heterozygote BALB/c mice was used to determine how T lymphocyte-deficient mice compared with normal mice in restricting proliferation of C. neoformans and to determine whether a correlation exists between delayed-type hypersensitivity and resistance to C. neoformans. Although nude mice displayed the ability to maintain cryptococcal population levels lower than did the phenotypically normal animals during the first 14 days of infection, the resistance was not sufficient to control the infection during the remainder of the 35-day experimental period. Heterozygote mice began to demonstrate positive delayed-type hypersensitivity responses by day 14 postinfection; however, nude mice were unable to mount delayed-type hypersensitivity responses. The appearance of the delayed-type hypersensitivity response in the heterozygote mice was concomitant with the reduced rate of proliferation of C. neoformans observed in those animals from days 14 to 35. Because anticryptococcal antibody titers and cryptococcal antigen levels were equivalent in both groups of mice, T-lymphocyte function was considered to be responsible for the resistance observed in the heterozygote mice. The mechanism by which cryptococcal populations were reduced was not addressed; however, the mouse model system used in these studies would be an ideal tool for studying those mechanisms. Nude mice were able to produce antibodies against cryptococcal cells, indicating that at least one component of C. neoformans is a T-independent antigen. The antibody response was predominantly immunoglobulin M in nude and heterozygote mice. Cryptococcal antigen levels were extremely high in both groups of animals and appeared to increase as C. neoformans cell numbers increased.