The influence of antibodies to recombinant murine tumor necrosis factor-alpha (anti—rMuTNF-α) on the development of the graft-versus-host reaction in vivo was investigated. This was done by evaluating the degree of splenomegaly in newborn BDF1(B6×DBA/2) mice 10–11 days after injection of autologous BDF1(controls) or semiallogeneic B6 (test) spleen cells. Splenomegaly, as reflected by the spleen index, among test BDF1mice was 3–4-fold greater than the SI of control BDF1mice. However, the treatment of test BDF1mice with multiple injections of rabbit anti-rMuTNF-α anti-serum resulted in a significant reduction in the SIs. In additional experiments, hamster monoclonal antibodies to rMuTNF-α were also shown to be effective in preventing the GVHR in vivo. Neither normal rabbit serum nor normal hamster IgG affected the GVHR in test BDF1mice. These results indicate that TNF-α plays an important role in the development of the GVHR in vivo and suggest that antibodies, or other antagonists, to TNF-α may have potential use for the management of organ or tissue transplants.