Background.Antibodies targeting recipient major histocompatibility complex (MHC) class II molecules have been demonstrated to be effective at prolonging allograft survival. However, antigen-presenting cell depletion would explain this effect and has not been definitively excluded as the mechanism of action of such antibodies. We have studied an anti-MHC class II antibody (OX6) proven to be noncytotoxic in the recipient strain used.Methods.Antibody was administered the day before, 2 hr before, and the day after grafting.Results.Antibody administration on the day before, 2 hr before, and the day after grafting significantly prolonged vascularized cardiac allograft survival. Importantly, treatment recognizing recipient MHC was effective, whereas a similar regimen recognizing donor MHC was not.Conclusions.Noncytotoxic recipient MHC class II-specific antibodies modify allograft rejection. Possible mechanisms for this therapeutic effect are discussed.