B cells, like T cells, show genetic restrictions in their interactions with other cells. B cells from (C3H/HeJ X C57BL/6J)F1 mice were stimulated with foreign antigen (sheep erythrocytes, SRBC) in parental-strain irradiated hosts. They could be subsequently activated to antibody formation in vitro by SRBC presented on cells of the same parental type, and much less by SRBC on cells of the other parental type. The restriction was seen whether antigen was presented on macrophages or by activated T cells. Experiments with congenic mice showed that the restriction was controlled by the MHC locus. Restriction of F1 B cells to responsiveness against either parental haplotype was much more readily induced in bone marrow than in splenic populations. This restriction could be broken down by giving the irradiated host a second injection of antigen 3 weeks after the first; this probably reflects "reeducation" of the F1 B cells by SRBC associated with donor, F1-type macrophages. Normal unprimed spleen B cells also showed a strong preference for activation by SRBC in association with syngeneic activated T cells.