To investigate the role of interferon (IFN)-γ in human cryptosporidiosis, jejunal biopsies from experimentally infected volunteers and chronically infected AIDS patients were examined for IFN-γ expression by in situ hybridization. IFN-γ expression was compared with oocyst excretion, baseline serum anti-Cryptosporidium antibody, and symptoms. IFN- γ mRNA was detected in biopsies from 13 of 26 volunteers after experimental infection but not in biopsies taken before C. parvum exposure or in biopsies from patients with AIDS-associated cryptosporidiosis. After challenge, 9 of 10 volunteers with baseline C. parvum antibody produced IFN-γ, compared with 4 of 16 volunteers without baseline antibody (P < .01). Furthermore, IFN-γ mRNA was detected in 9 of 13 volunteers who did not excrete oocysts, compared with 4 of 13 with organisms (P< .05). Thus, expression of IFN-γ in the jejunum was associated with prior sensitization and absence of oocyst shedding. IFN-γ production may explain the resistance to infection noted in sensitized persons but may not be involved in control of human primary infection.