After small bowel transplantation, not only rejection but also graft-versus-host reaction (GVHR) may occur. Donor T lymphocytes, transferred together with the graft, are a prerequisite for the development of GVHR. So far, however, little is known about the effector mechanisms in acute GVHR. It can be assumed that not only T lymphocytes but also other cells, i.e., B lymphocytes, monocytes/macrophages, and NK cells, together with inflammatory cytokines, are responsible for the lesions of recipient tissue. In the present study, the occurrence of recipient-reactive antibodies after semisyngeneic small bowel transplantation was investigated to elucidate the role of B lymphocytes in GVHR development. No antibodies reactive with recipient cells were detectable in serum from untreated, nontransplanted rats. Five days after transplantation, recipient-reactive antibodies started to appear in recipient serum. At the same time, a deposition of IgM antibodies became visible in the liver and native intestine, which are target organs for GVHR. No antibodies directed against either the donor strain or a third-party strain were detectable in serum. We conclude that a synthesis of antibodies against recipient tissue occurs during the development of GVHR. Whether these antibodies contribute to the disease remains unclear.