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Infection with Cryptosporidium spp. causes diarrhoeal disease and has become an important medical and veterinary problem especially in the immunocompromised host. The importance of the adaptive immune response, with CD4+ T-lymphocytes being the major players, has been clearly demonstrated. The requirement of IL-12 and IFN-gamma identifies this response as a Th1-dominated reaction. IFN-gamma is also important in the early phase of the host-parasite interaction. We analysed the outcome of infection in IL-12p40 (IL-12KO) and IFN-gamma (GKO) deficient C57BL/6 mice after primary and secondary challenge with the parasite and, for the first time, we demonstrate the resulting Ig response in sera and vaginal lavages. Although showing differences in the extent and the time course both strains of mice were able to clear infection and developed an almost complete resistance to re-infection. While GKO mice mounted prolonged parasite-specific IgG and IgA responses after primary infection, in IL-12KO mice IgG and IgA titres dropped over time. Re-challenge of mice 5 weeks after primary infection led to a booster effect in Ig response despite the absence of oocyst shedding. The data from infection and re-challenge experiments suggest that in IL-12- or IFN-gamma-deficient mice the development of resistance involves other protective immune responses.