We analyzed the in vitro xenoreactivity of human and different Old World primate species against freshly isolated adult pig islets. Incubation of purified islets with human serum showed IgG, IgM and IgA binding which did not increase after four days of culture. Incubation with up to 50% human sera resulted in C3, C4 and MAC (but not fB) deposition on pig islets. Nevertheless, islets were not lysed, as evaluated by 51Cr release. Islets cultured for up to 4 days in 50% human serum showed a normal microscopic morphology and a preserved insulin production in response to glucose stimulation. Immunohistology revealed binding of IgG, IgM, C9 and C4 but not fB on Galα(1-3)Gal-positive intraislet cells as determined by double staining with IB4 lectin. These cells (10-15%) were identified as endothelial cells (EC) by vWF staining. Pig islets incubated with different chimpanzee and M. rhesus sera resulted in IgG and IgM fixation by cytofluorometry analysis. No islet cytotoxicity was observed after incubation with chimpazee serum, but islets were lysed between 15 and 50% by allM. rhesus (n=7), baboon (n=5) and M. fascicularis (pool) sera tested. Lysis of porcine EC was obtained with all human and primate sera tested between 30 and 80%. Analyses of pig islets incubated with Old World primate sera showed IgG and IgM binding on intraislet EC but not on β cells. In conclusion, although pig islets incubated with human or Old World primate sera showed a similar profile for IgG and IgM fixation on intraislet EC (not on β cells), striking differences were observed in their ability to lyse pig islets. Concerning islets, the pig-to-chimpanzee combination closely resembles human anti-pig in vitro xenoreactivity.