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Objectives: In spite of the extensive research, the exact mechanism of graft rejection remains not well understood. Since the recipients which have inactivated all known mechanisms of T cell-mediated cytotoxicity can reject allografts, the graft infiltrating macrophages have been considered as a potential effector cell population capable to reject incompatible allografts. Methods: Skin grafts were transplanted in mice in fully allogeneic strain combination or in xenogeneic system and the production of nitric oxide (NO) by graft infiltrating macrophages was determined in graft explants. Results: A significant production of NO was found in rejected allografts and xenografts. The production of NO in graft explants was dependent on the presence of alloimmune T cells and was inhibited by the specific inhibitors of inducible NO synthase. Treatment of allograft recipients with inhibitors of NO synthase enhancedgraftssurvival.Conclusions: T cell-dependent production of NO by graft infiltrating macrophages may represent at least one of the effector mechanisms of allograft and xenograft rejection.