Lymphotoxin α-deficient (LTα(-/-)) mice show dramatically reduced IgG responses after either primary or secondary immunizations with sheep red blood cells (SRBC). When splenocytes from SRBC-primed wild-type donor mice were infused into irradiated naive wild-type recipient mice, they generated a robust memory IgG response, but not when infused into LTα(-/-) recipients, indicating that the microenvironment that develops in LTα(-/-) mice is incompetent to support the activation of this memory response. When irradiated wild-type mice were reconstituted with splenocytes from primed LTα(-/-) donors and then challenged with the same immunizing Ag, no memory response was observed, indicating further that memory cells could not be generated in the LTα(-/-) environment. To address which lymphocyte subsets were impaired in the LTα(-/-) mice, we performed reconstitution experiments using a hapten/carrier system and T cells and B cells from different primed donors. There was no detectable defect in either the generation or expression of memory T cells from LTα(-/-) donors. In contrast, B cells were not primed for memory in the microenvironment of LTα(-/-) mice. Additionally, primed wild-type memory B cells could not express a memory IgG response in the LTα(-/-) microenvironment. Thus, splenic white pulp structure, which depends on the expression of LTα for its development and maintenance, is needed to support the generation of memory B cells and to permit existing memory B cells to express an isotype switched memory Ig response following antigenic challenge.