In vivo TNF inhibition has been observed to ameliorate the disease process attributed to T cell‐dependent immune responses such as those generated during graft‐vs.‐host disease. The present studies were designed to evaluate whether TNF/TNF receptor (TNFR)1 and TNF/TNFR2 interactions were involved in the generation of allospecific T cell responses. Splenic lymphocyte populations were obtained from TNFR1‐ or TNFR2‐deficient B6 mice and from control B6 mice. These responder cells were cultured with irradiated MHC class II‐disparate B6.C‐H‐2^bm12 (bm12) or MHC class I‐disparate B6.C‐H‐2^bm1 (bm1) or irradiated syngeneic stimulator cells for 3 days before assay of [³H]thymidine incorporation. IL‐2 levels of the mixed lymphocyte culture (MLC) supernatants were assessed by enzyme‐linked immunosorbent assay. With MHC class II‐disparate bm12 stimulator cells, a significant reduction in T cell proliferation was observed utilizing TNFR2‐deficient CD4⁺ responder T cells, but not when using TNFR1‐deficient CD4⁺ responder T cells. A significant decrease in proliferation of TNFR1‐deficient CD8⁺ responder cells, but not of TNFR2‐deficient CD8 responder T cells was observed after stimulation with MHC class I‐disparate bm1 stimulator cells. IL‐2 levels were lower in MLC utilizing MHC class I stimulators and TNFR1‐deficient responders or MHC class II stimulators and TNFR2‐deficient responders. These results indicate that TNF/TNFR2 interactions promote MHC class II‐stimulated alloresponses, while TNF/TNFR1 interactions promote MHC class I‐stimulated alloresponses.