The genetic control of the murine T [thymus derived] cell proliferative response to insulin was examined. Two responder strains of mice each recognize a different determinant on the insulin molecule. H-2b mice recognize a determinant in the A chain loop of insulin whereas H-2d mice recognize a determinant that resides in the B chain, possibly in the last 8 amino acids. Using H-2 recombinant strains of mice, the location of Ir gene control of the response to both determinants was mapped to the K region and/or I-A subregion of H-2. The possibility of non-MHC [major histocompatibility complex] regulation of MHC-controlled immune responses was suggested by studies of recombinant inbred strains of mice.