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Gpr97 is an orphan adhesion GPCR and is highly conserved among species. Up to now, its physiological function remains largely unknown. Here, we show that Gpr97 deficiency results in an extensive reduction in B220+ lymphocytes in mice. More intensive analyses reveal an expanded marginal zone but a decreased follicular B-cell population in Gpr97−/−spleen, which displays disorganized architecture characterized by diffuse, irregular B-cell areas and the absence of discrete perifollicular marginal and mantle zones. In vivo functional studies reveal that the mutant mice could generate antibody responses to T cell-dependent and independent antigens, albeit enhanced response to the former and weakened response to the latter. By screening for the molecular events involved in the observed phenotypes, we found that lambda 5 expression is downregulated and its upstream inhibitor Aiolos is increased in the spleen of mutant mice, accompanied by significantly enhanced phosphorylation and nuclear translocation of cAMP response element-binding protein. Interestingly, increased constitutive Nf-κb p50/p65 expression and activity were observed in Gpr97−/− spleen, implicating a crucial role of Gpr97 in regulating Nf-κb activity. These findings uncover a novel biological function of Gpr97 in regulating B-cell development, implying Gpr97 as a potential therapeutic target for treatment of immunological disorders.