Normal B10.BR (H-2k, C57B1/6 background) spleen cells, enriched in primary mixed lymphocyte culture (MLC) for antigens of C3H/Tif mice (H-2k, C3H background), induced normal C3H/Tif but not B10.BR B lymphocytes to proliferate and produce Ig. In contrast, normal B10.BR spleen cells enriched in parallel B10.BR anti-C57B1/6 (H-2b) MLC were not able to activate either B10.BR or C57B1/6 B lymphocytes. However, normal B10.BR spleen cells depleted of Lyt2+ cells before initiation of the MLC, and subsequently enriched either for C3H/Tif or C57B1/6 antigens, activated B lymphocytes of the respective mouse strains specifically and equally well. These experiments show that primary MLC gives rise to effector T helper cells that, on recognition of specific alloantigens, activate normal B lymphocytes of the 'stimulator' strain. In response to major histocompatibility complex (MHC) alloantigens, this help is not revealed because of interference by Lyt 2+ lymphocytes. MHC-reactive T helper cells for B lymphocytes, however, participate in these reactions and constitute the predominant population in long-term cultures that are maintained by consecutive in vitro restimulations.