Peyer's patches (PP) have been considered to be major inductive sites for the initiation of the mucosal IgA responses in the gut. In this study, we have assessed the importance of PP for mucosal IgA response. When tumor necrosis factor (TNF) and lymphotoxin (LT)-α double knockout (TNF/LT-α-/-) mice, which lack both PP and mesenteric lymph nodes (MLN) were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) as mucosal adjuvant, neither mucosal IgA nor serum IgG anti-OVA antibodies were induced although subcutaneous immunization of TNF/LT-α-/- mice with OVA plus CT induced antigen-specific serum IgG responses. Interestingly, blocking the LT-β receptor (LTβR) of normal mice with fusion protein of LTβR and immunoglobulin (LTβR-Ig) produces mice that lack PP but not MLN and that elicited OVA-specific mucosal IgA as well as serum IgG antibody responses after oral immunization. OVA-specific CD4+ T cells with Th2 phenotype were induced in MLN and spleen of LTβR-Ig treated mice. These results indicate that if draining lymph nodes such as MLN exist, organized PP are not required for mucosal IgA antibody responses in the intestine.