Vigorous lymphocyte proliferative response to synthetic polypeptides was observed in cells from 50 normal volunteers. Results indicated that 64% responded to poly(LHis, LGlu)-poly(DLAla)--poly(LLys) [(H, G)-A--L] and 54% to poly(LTyr, LGlu)-poly(DLAla)--poly(LLys) [(T, G)-A--L]. Subjects could be classified into high-, intermediate-, and non-responder phenotypes according to their stimulation indices. Family studies indicated that high responses to these antigens are inherited as histocompatibility antigen gene (HLA)-linked dominant traits. Two matings suggested gene complementation in response to (T, G)-A--L and (H, G)-A--L. One, with an intra-HLA recombinant offspring, provided evidence localizing the immune response gene(s) controlling lymphocyte proliferation to (T, G)-A--L and (H, G)-A--L, presumably the homologue to Ir-1 of mouse, closer to the HLA-B than to the HLA-D region.