The central function of murine CD83 that is expressed on thymic epithelial cells is to induce the progression of double-positive thymocytes to single CD4-positive T cells. Several lines of evidence suggest an additional role for CD83 in the regulation of peripheral T and B cell responses. Here we show that CD83 is expressed by immature B cells and regulates their further maturation and survival in the periphery. Employing mixed bone marrow chimeras, we compare wild-type, CD83 over-expressing and CD83-deficient B cells within the same host. CD83 over-expression on the immature B cells themselves led to an accumulation of transitional B cells and a reciprocally reduced maturation of follicular B cells that was strictly correlated to the intensity of CD83 over-expression. The absence of CD83 on B cells resulted in a decreased maturation of marginal zone B cells and conferred a mild selection advantage for B cell survival in the periphery. Consenting with these findings, the over-expression of CD83 specifically and dose dependently interfered with homeostasis of B cells while T cell survival was not affected by CD83 over-expression over a period of 30 weeks. Taken together, our data suggest that CD83 negatively regulates B cell maturation and survival.