The role of secondary lymphoid organs in adaptive immune responses following transplantation is controversial. To examine the requirement for peripheral lymphoid organs in mounting immune responses to transplantation antigens, lymphotoxin α-deficient (LTα–/–) and LTβ-receptor-deficient (LTβR–/–) mice that lack lymph nodes and Peyer's patches were used as recipients of fully allogeneic heart and skin grafts. Splenectomized LTα–/– and LTβR–/– mice effectively rejected skin and cardiac allografts, although with delayed kinetics when compared with wild-type controls. In addition, initial skin allograft challenge in splenectomized LTβR–/– mice resulted in accelerated rejection of subsequent donor cardiac allografts when compared with heart rejection in nonsensitized controls. Thus, although peripheral lymphoid organs play an important role in allowing allograft responses to occur, they do not appear to be absolutely required for either acute allograft rejection, or T-cell priming. These results suggest that immunologic events capable of leading to allograft rejection can successfully occur at sites other than classical secondary lymphoid organs.