Severe cryptosporidial infections were produced in gamma interferon (IFN-γ) knockout mice. Mean oocyst shedding increased from 332 to 30717 oocysts/100 μl of faecal suspension between day 4 and 9 after administration of 1×105 oocysts/mouse. No significant differences in oocyst shedding were observed in mice after being inoculated with 1×105, 1×104 or 1×103 oocysts/mouse (P>0·05). Infected mouse weights decreased an average 3–4 g before death or euthanization. Histological studies revealed heavy parasite colonization in small intestinal epithelium (approximately 250 organisms/high-power field at ×400). Mesenteric lymph nodes in infected mice were markedly enlarged compared to controls (P<0·05). Both CD4+ and CD8+ T cell populations increased in spleens of infected mice while the B cell population increased in mesenteric lymph nodes from infected mice. No significant proliferation was observed when pooled lymphocytes from infected mice were exposed to C. parvum antigens in vitro. Addition of recombinant mouse IFN-γ did not restore antigen responsiveness. While lymphoproliferative responses to specific antigen were not significant in the short period following infection, this mouse model provides unique features to study the characteristics of acute infection and the immune response against C. parvum.