Cryptosporidium parvum preparations were studied for their ability to induce specific proliferation of cultured human peripheral blood mononuclear cells (PBMC) from both immunocompetent and human immunodeficiency virus-positive persons, some of whom had transient cryptosporidiosis. The proliferation of PBMC from sensitized donors induced by C. parvum preparations was due mainly to antigen-specific rather than nonspecific activation, as indicated by the kinetics of the proliferative response, inhibition of the PBMC proliferation by a monoclonal antibody directed against major histocompatibility complex class II-specific HLA-DR molecule, and lack of proliferation of umbilical cord blood PBMC. PBMC from immunocompromised patients did not proliferate in response to C. parvum-specific antigens. The supernatants of PBMC obtained from immunocompetent donors contained interleukin-10 and interferon (IFN)-gamma after PBMC were exposed to C. parvum preparations. High IFN-gamma values were found in patients who had recovered from cryptosporidiosis, suggesting that IFN-gamma plays a role in resolving this infection.