Indoleamine 2,3 dioxygenase (IDO) activity during pregnancy protects developing fetuses from maternal immune responses in CBA mice. We show here that fetal allografts were rejected only in mating combinations where paternally inherited tissue antigens elicited potent maternal T cell responses after exposure to IDO inhibitor. IDO inhibitor treatment triggered extensive inflammation at the maternal-fetal interface in susceptible mating combinations, which was characterized by complement deposition and hemorrhagic necrosis. Identical inflammatory responses occurred in B cell-deficient (RAG-I-/-) mothers that carried a monoclonal cohort of CD8+ T cells specific for a single paternally inherited fetal major histocompatibility complex antigen. Thus, fetal allograft rejection was accompanied by a unique form of inflammation that was characterized by T cell-dependent, antibody-independent activation of complement. In contrast, no inflammation, complement deposition or T cell infiltration was elicited when mice carrying syngeneic fetuses were exposed to IDO inhibitor. These data show that IDO activity protects the fetus by suppressing T cell-driven local inflammatory responses to fetal alloantigens.