Anti-CD4, anti-CDS, or anti-interferon-γ (IFN-γ) antibodies or combinations of them were administered in the early stages of chronic infection of mice with a Candida albicans live vaccine strain, and the animals were monitored for course of primary infection, development of delayedtype hypersensitivity, resistance to reinfection, production of interleukin 2 (IL-2) and IFN-γ in vitro by splenic lymphocytes, and levels of IL-2 and IFN-γ transcripts in these cells. CD4+ cell and IFN-γ depletion resulted in the development of fatal candidiasis by the attenuated yeast vaccine. In contrast, either treatment alone modified the course but not the outcome of primary infection, though each prevented the development of resistance to reinfection. Our data thus indicate that both IFN-γ and CD4+ cells participate in resistance to primary infection with attenuated yeast cells and are critical in the induction of persistent systemic anticandidal immunity.