Complement receptor 2 (CR2) participates in the regulation of B cell responses to antigen. In this study we report that treatment of IM-9 B lymphoblastoid cells or Raji Burkitt's lymphoma cells with 10% heat-inactivated fetal bovine serum for 24 hr increased both the CR2 mRNA level and CR2 surface protein expression more than two-fold. No change in the CR2 expression level was observed if cells were cultured in serum-free medium. The CD19 mRNA level decreased after 24 hr independently of the presence of serum. The serum-stimulated increase in CR2 expression was not due to changes in the proliferative capacity of the cells and could not be mimicked by various cytokines. However, IFN-gamma as well as OKB7, a CR2-specific monoclonal antibody, blocked the serum-induced increase in CR2 expression at the mRNA level. Our data show for the first time that factors in serum induce the expression of the CR2 gene and that signals initiated by IFN-gamma and OKB7 interfere with the serum-induced changes. Because stimuli that alter CR2 expression can influence the extent of the B cell response to antigen-C3d complexes, serum factors may play a role in regulating the responsiveness of B cells.