The recent introduction of a reliable, T-lymphocyte proliferation assay, which utilizes thioglycollate-induced, nylon wool column-passed, peritoneal exudate lymphocytes from immune mice (PETLES), allowed us to investigate the genetic control of murine immune responses at the T-lymphocyte level. Examination of the blast cells generated in this population 5 days after stimulation with antigen, revealed that 85% of the cells bore the Thy 1 antigen on their surface, whereas only 5% bore immunoglobulin. Thus, the assay can be considered to measure almost exclusively T-lymphocyte function. This assay was used to examine the T-lymphocyte proliferative responses to seven different antigens: poly(Glu60Ala30Tyr10), poly(Glu58Lys38Tyr4), poly-(Tyr,Glu)-poly-D,L-Ala--poly-Lys, poly-(Phe,Glu)-poly-D,L-Ala--poly-Lys, staphylococcal nuclease, lactate dehydrogenase H4, and the BALB/c IgA myeloma protein, TEPC-15. PETLES from a large number of different inbred mouse strains, including H-2 congenic resistant lines and H-2 recombinants, were studied. The strains could be classified as high responders, low responders, or nonresponders to a particular antigen as judged by the magnitude of the T-lymphocyte proliferative response. In every case but one this classification corresponded to the responder status given the strain based on its ability to mount an in vivo antibody response to the same antigen. For two of the antigens, poly-(Tyr,Glu)-poly-D,L-Ala--poly-Lys and TEPC-15, the immune response genes controlling the T-lymphocyte proliferative response were mapped to the K region or I-A subregion of the major histocompatibility complex, as had previously been shown for the control of the antibody responses to these antigens. This tight linkage of the two phenotypic responses very strongly suggests that the same immune response gene controls the expression of both the proliferative and antibody responses. Since there is essentially no contribution from B lymphocytes in the T-lymphocyte proliferation assay, it seems reasonable to conclude that none of the seven immune response genes studied are expressed solely in B lymphocytes.