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Cryptosporidiosis is an important cause of diarrhea worldwide. In normal hosts, infection is self-limited and associated with seroconversion and partial immunity to reinfection. Immunity is associated with interferon gamma (IFNγ) production. Cryptosporidium surface proteins gp15 and gp40 are among the immunodominant proteins in terms of antibody responses. We asked the question of whether these antigens also stimulate production of IFNγ in patients who have serologic evidence of prior infection. Whole blood from seropositive donors was stimulated with recombinant gp15 and gp 40 from Cryptosporidium hominis and Cryptosporidium parvum or His-tag controls. C. hominis gp15 stimulated increased production of IFNγ. By contrast, there was no significant increase after stimulation with C. parvum gp15 or either gp40 preparation. IFNγ production in response to C. hominis gp15 was noted in both CD4+ and CD8+ cells. This highlights the potential for C. hominis gp15 as a vaccine candidate for human cryptosporidiosis.