Experimental inoculation of neonatal immunocompetent strains of mice with Cryptosporidium parvum results in a transient, noninflammatory enteric infection. In the present study, we show that inoculation of mice deficient in αβ and γδ T cells (TCR-β- x TCR-δ-deficient Mice) with C. parvum results in persistent infection and severe inflammatory bowel disease-like lesions. The most severe lesions in these mice were in the cecum with similar yet less severe lesions in the ileum and proximal colon. The most notable aspect of the histopathology was glandular hyperplasia with abscess formation, extensive fibrosis of the lamina propria with infiltrates of predominately polymorphonuclear cells and macrophages, and a few small aggregates of B cells. Persistently infected mice also developed extensive hepatic periportal fibrosis in association with C. parvum colonization of bile ducts. Lesions observed in TCR-β- x TCR-δ-deficient mice were markedly different than previously described lesions detected in C. parvum-infected TCR-α -deficient mice. Cryptosporidium parvum-infected TCR-α-deficient mice have extensive infiltrations of B cells, whereas TCR-β x TCR-δ -deficient mice had only a few small aggregates of B cells. These findings indicate that although γδ T cells are not necessary for induction of intestinal inflammation in C. parvum-infected αβ T- cell-deficient mice, their presence does alter the morphology of the ensuing lesion.