Mice with targeted disruptions in the T-cell receptor α gene (TCRα^−/−) spontaneously develop inflammatory intestinal lesions with extensive B-cell lamina propria infiltrates. Cryptosporidium parvum infection accelerates intestinal lesion formation in TCRα^−/− mice. In the present study, TCRα^−/− mice were crossed with JH^−/− (B-cell-deficient) mice and challenged with C. parvum to determine if B cells are required for intestinal lesion development. TCRα^−/− × JH^−/− mice challenged with C. parvum, either as neonates or adults, became persistently infected, whereas TCRα^−/ × JH^−/ heterozygote control mice cleared the parasite. Cryptosporidium parvum colonization of TCRα^−/− × JH^−/− mice was heaviest in the distal ileum, with fewer parasites detected in the cecum and distal colon. Despite persistent infection, TCRα^−/− × JH^−/− mice did not develop inflammatory or hyperplastic intestinal lesions as detected in C. parvum-infected TCRα^−/− mice. These findings demonstrate that B cells are a necessary component for the development of inflammatory intestinal lesions of C. parvum-infected TCRα^−/− mice.