This study describes healing and nonhealing models of Cryptosporidium parvum infection with adult mice that have functional T and B lymphocytes. In our nonhealing model, mice on a C57BL/6 background which have a targeted disruption in the gamma interferon (IFN-gamma) gene (GKO mice) are utilized. C. parvum-infected GKO mice shed extremely high levels of oocysts and displayed overwhelming infection of the entire small intestine. The majority of these mice succumbed within 2 to 3 weeks due to severe acute infection and profound mucosal destruction. In our healing murine model, C57BL/6J mice treated with a single injection of the neutralizing anti-IFN-gamma monoclonal antibody XMG 1.2 prior to infection were used. These mice developed two peaks of oocyst shedding but were ultimately free of parasites on day 30 of infection. Again, the small intestine was the primary site of infection. Mesenteric lymph node (MLN) cells isolated from C. parvum-infected nonhealing GKO mice proliferated and secreted interleukin 2 (IL-2) but not IFN-gamma or IL-4 in response to ex vivo restimulation with intact C. parvum sporozoites or a C. parvum sporozoite antigen preparation. In contrast, parasite-specific MLN cells isolated from healing C57BL/6J mice secreted IL-2 and IFN-gamma but not IL-4. These results suggest that IFN-gamma, either directly or indirectly, is important for resistance to and resolution of cryptosporidiosis. Moreover, these models now allow the analysis of parasite-specific cell-mediated and humoral mucosal immune responses to determine what constitutes protective immunity to C. parvum.