Mucosal tissues of mice are enriched in T cells that express the γ/δ T cell receptor. Since the function of these cells remains unclear, we have compared mucosal immune responses in γ/δ T cell receptor-deficient (TCRδ(- /-)) mice versus control mice of the same genetic background. The frequency of intestinal immunoglobulin (Ig) A plasma cells as well as IgA levels in serum, bile, saliva, and fecal samples were markedly reduced in TCRδ(-/-) mice. The TCRδ(-/-) mice produced much lower levels of IgA antibodies when immunized orally with a vaccine of tetanus toxoid plus cholera toxin as adjuvant. Conversely, the antigen-specific IgM and IgG antibody responses were comparable to orally immunized control mice. Direct assessment of the cells forming antibodies against the tetanus toxoid and cholera toxin antigens indicated that significantly lower numbers of IgA antibody-producing cells were present in the intestinal lamina propria and Peyer's patches of TCR(-/-) mice compared with the orally immunized control mice. The selective reduction of IgA responses to ingested antigens in the absence of γ/δ T cells suggests a specialized role for γ/δ T cells in mucosal immunity.