The helper activity of allogeneic effect factors (AEF) derived from mixed lymphocyte culture reactions (MLR) between activated responder cells and either I-region, I-subregion, or Mls-region incompatible irradiated stimulator spleen cells was analyzed. An AEF generated across either an a) entire I-region, b) I-A, I-B and I-J, c) I-J or d) I-E and I-C subregion incompatibility helps B cells of only the stimulator haplotype, or of haplotypes which carry I-subregions selectively expressed by the stimulator cells and not the responder cells. An AEF generated across an Mls-region difference provides weak help for B cells only of haplotypes which share both an Mls and I-region identity with the stimulator haplotype. The observed lack of help for B cells of the responder haplotypes is not due to a suppressor factor activity in these H-2 restricted AEFs. These results are consistent with those obtained for another genetically restricted AEF produced by Ia negative activated responder cells and H-2 incompatible irradiated T-cell-depleted stimulator cells.