Advances in the field of xenotransplantation raise the intriguing possibility of using porcine red blood cells (pRBCs) as an alternative source for blood transfusion. The domestic pig is considered the most likely donor species for xenotransplantation. However, identification of xenoantigens on porcine erythrocytes and elucidation of their possible roles in antibody-mediated RBC destruction are necessary for developing clinical strategies to circumvent immunological incompatibility between humans and pigs. Although the alphaGal epitope (Galalpha1,3Galbeta1,4GIcNAc-R) is the major xenoantigen on porcine erythrocytes and is responsible for the binding of the majority of human natural antibodies, other non-alphaGal xenoantigens have been identified. The importance of these non-alphaGal xenoantigens in binding human natural antibodies and subsequently triggering immunological responses cannot be underestimated. Our data suggest that non-alphaGal xenoantigen(s) identified on the porcine erythrocyte membrane are not only recognized by xenoreactive human natural antibodies but are also involved in complement-mediated hemolysis.