In order to examine whether the H-2 haplotype of a thymus graft influences the levels of IgG3, IgG1, IgG2b, and IgG2a antibodies produced in an in vivo response to antigens under immune response (Ir) gene control, genotypic high-responder (H-2b X H-2k)F1.nude mice were grafted with thymuses from irradiated, neonatal low-responder (H-2k) or high-responder (H-2b or (H-2k X H-2b)F1) mice and immunized with (T,G)-A--L. All IgG antibody responses to (T,G)-A--L in high-responder mice were shown to be thymus dependent. The majority of F1.nude mice grafted with thymuses from high-responder haplotype donors produced high-responder levels of IgG anti-(T,G)-A--L antibodies. Conversely, the majority of F1.nude mice grafted with thymuses from low-responder haplotype donors gave low-responder phenotypic patterns. The modulation of the Ir gene phenotype was not restricted to a particular IgG isotype, but affected IgG3, IgG1, IgG2b, and IgG2a. The F1 . nude mice grafted with low-responder haplotype thymuses were able to produce IgG1, IgG3, and IgG2b antibodies to sheep erythrocytes, a thymus-dependent (TD) antigen not under overt Ir gene control. Circulating peripheral T cells were shown to be of host origin. By these criteria, the thymus grafts did enable F1.nude mice to respond to a TD antigen. These results support the concept that thymic H-2 determinants are involved in at least the selection of H-2 restricted T cell subsets, if not also the derivation of the T cell receptor repertoire for self and/or antigen recognition.