BALB/c splenocytes stimulated in vitro with trinitrophenyl (TNP)-modified syngeneic cells inhibit the secretion of antibody by the TNP-binding BALB/c myeloma MOPC 315 in the presence of soluble TNP-Keyhole limpet hemocyanin (KLH). The effector cells are hapten-specific, H-2-restricted, Thy-1.2-bearing, Ly-2-positive T lymphocytes whose precursors are resistant to pretreatment with cyclophosphamide. These phenotypic properties are typical of hapten-specific cytolytic T lymphocytes (CTL). The TNP-reactive CTL that inhibit MOPC 315 cells fail to suppress H-2d myelomas that do not bear TNP-specific surface receptors, and this is not attributable to differences in total binding of TNP-KLH to the different myeloma cells. Moreover, azobenzene arsonate (ABA)-specific CTL inhibit MOPC 315 cells in the presence of the double conjugate TNP-ABA-KLH, but not in the presence of soluble TNP-KLH or ABA-KLH. These results show that H-2-restricted, hapten-specific lymphocytes regulate the function of myeloma cells that bind the hapten only to specific surface receptors, and provide a model for associative recognition of surface H-2 determinants and receptor-bound antigen. The results are discussed with reference to the mechanisms of T lymphocyte-target cell interactions, and the possible physiologic role of hapten-reactive CTL in specifically regulating anti-hapten antibody responses.