The antibody response to poly-(Glu53Lys36Phe11) (GLphi) has been shown to be under the control of two independent, major histocompatibility-linked immune response genes, designated alpha and beta. In the present work we demonstrate that the T-lymphocyte proliferative response is also under the control of these two immune response genes. Thus, mice of the H-2a, H-2b, H-2k, and H-2s haplotypes were all nonresponders to GLphi. In contrast F1 hybrids between these strains, such as (B10 X B10.A)F1 and (C3H X SJL)F1, as well as several recombinant mice derived from the nonresponder haplotypes, such as B10.1(5R), B10.HTT, and B10.S(9R), were all responders to GLphi. The complementation between nonresponder genomes appeared to be stronger in the cis position than in the trans position for some strain combinations. The failure of strains bearing only one of the two responder alleles to show a T-lymphocyte proliferative response to GLphi, argues strongly that neither gene can be expressed exclusively in B lymphocytes. This conclusion is discussed in relation to another two gene model which has recently been proposed.