Two mechanisms could account for the impaired humoral immune response found in Cr2−/− mice. The absence of complement receptors 1 and 2 (CR1, CR2) on B cells could affect their activation. Alternatively, impaired Ag trapping by follicular dendritic cells (FDC) could affect B cell maturation into Ig-secreting or memory B cells. To compare the roles of CR1 and CR2 on B cells vs FDC in this abnormal response, bone marrow (BM) chimeric mice were generated and immunized with specific T-dependent Ags. The primary and secondary Ab response was measured. Cr2+/+ animals reconstituted with a Cr2−/− BM generated a diminished but detectable humoral immune response compared with controls. When injected with preformed immune complexes (IC), these mice maintained follicular IC localization. Cr2−/− animals reconstituted with a Cr2+/+ BM had an initial rise in the Ab titer, but were unable to maintain it as shown by a pronounced decrease in the IgG titer. This defect persisted during the secondary immune response. Follicular IC trapping was also impaired. Despite the abnormal Ab response, germinal center formation was retained in all of the chimeric animals. These experiments are the first to demonstrate an absolute requirement for CR1 and CR2 expression on FDC in the generation of a normal humoral immune response.