We compared the effects of in vivo administration of the anti-T-cell receptor (TCR) alpha beta monoclonal antibody (mAb) (H57-597) to those of the anti-CD3 mAb (145-2C11), with or without anti-NK1.1 mAb (PK136), on xenogeneic skin graft survival in mice. In anti-TCR alpha beta mAb-treated B6 mice, F344 rat skin grafts survived for about 54 days, whereas in anti-CD3 mAb-treated B6 mice with or without anti-NK1.1 mAb treatment grafts survived about 25 days. In anti-TCR alpha beta mAb-treated B6 mice, TCR alpha beta-bearing T-lymphocyte function was completely abrogated, although TCR gamma delta-bearing T-lymphocyte function was still intact on day 9. In the anti-CD3 mAb-treated mice, the functions of both types of T lymphocytes were completely abrogated. On day 32, when most of the skin xenografts had been rejected in the anti-CD3 mAb-treated mice, the functions of both T lymphocytes had recovered considerably, and could actually respond to F344 antigens. In contrast, the function of TCR alpha beta-bearing cells had only partially recovered in the anti-TCR alpha beta mAb-treated mice. Finally, natural killer (NK) activity in the anti-TCR alpha beta mAb-treated mice was intact on day 32, when rat skin grafts still survived. In contrast, NK activity in the anti-CD3 mAb plus anti-NK1.1 mAb-treated mice did not recover on day 32, when skin xenografts had already been rejected. These results suggest that TCR gamma delta-bearing T cells and NK cells by themselves, at least in the absence of TCR alpha beta-bearing T cells, do not mediate xenogeneic skin graft rejection in mouse/rat combinations.