SCID mice, which lack T and B cells, were used as hosts to investigate the nature of both T cell-independent and T-cell-dependent immune responses to infection with Cryptosporidium parvum. We found previously that SCID mice developed chronic infections in which the level of oocyst excretion was low up to about eight weeks post-infection but then increased significantly to cause morbidity and death after 13 weeks. In the present study, weekly administration of an anti-IFN-gamma monoclonal antibody (MoAb) resulted in a shortened prepatent time, significant increase in oocyst excretion and early onset of disease and death. These results suggested an immunologically mediated resistance to C. parvum in the SCID host which required the production of IFN-gamma. Attempts to demonstrate a role for TNF in nonspecific immunity were unsuccessful as injection of mice at weekly intervals with an anti-TNF MoAb failed to alter the course of infection. In contrast to the chronic infection observed in the mice above, SCID mice reconstituted with spleen cells from naive BALB/c mice were able to recover. Depletion of CD4+ cells from the donor population abrogated this protective effect. Mice receiving spleen cells depleted of CD8+ cells were able to recover but the patent infection was prolonged compared with those obtained in mice receiving unfractionated cells. These results demonstrate that CD4+ cells are necessary for the development of immunity to C. parvum infection in reconstituted SCID mice, but, in addition, that CD8+ cells also make a significant contribution to this immunity.