Although CD4 T cells are required for recovery from cryptosporidial infection, mice with severe combined immunodeficiency (SCID) remain infected for long periods without ill effect. In contrast, mice whose ability to use interferon(IFN)-gamma is impaired, by neutralization or gene knockout, experience heavy cryptosporidial infection that may lead to death. To determine whether the innate immunity of SCID mice to Cryptosporidium parvum (CP) requires IFN-gamma, doubly immunodeficient C57BL/6 SCID-IFN-gamma knockout mice were bred. These mice experienced heavy CP infections of the gut; a significantly greater number became moribund or died, compared with mice carrying the SCID mutation alone or carrying disrupted IFN-gamma genes alone. Mice with gene disruptions of inducible nitric oxide synthetase or Fas/Fas ligand recovered normally from CP infection. The results indicate that mice unable to produce specific immune responses because of the SCID mutation require IFN-gamma to avoid death after infection with CP.