Lymphotoxin β receptor (LTβR)^−/− mice were created by gene targeting. LTβR^−/− mice lacked Peyer's patches, colon-associated lymphoid tissues, and all lymph nodes. Mucosa patrolling α_Eβ₇^high integrin⁺ T cells were virtually absent. Spleens lost marginal zones; T/B cell segregation and follicular dendritic cell networks were absent. Peanut agglutinin⁺ cells were aberrantly detectable around central arterioles. In contrast to TNF receptor p55^−/− mice, antibody affinity maturation was impaired. Since LTβR^−/− mice exhibit distinct defects when compared to LTα^−/− and LTβ^−/− mice, it is suggested that the LTβR integrates signals from other TNF family members. Thus, the LTβR proves pivotal for the ontogeny of the secondary lymphoid tissues. Furthermore, affinity maturation is dependent on LTα₁β₂ rather than on LTα₃.