The capacity of vascularized xenografts to survive in the face of normal levels of circulating antigraft antibodies and complement has been ascribed to a phenomenon referred to as "endothelial cell accommodation." The mechanisms whereby accommodation might occur have remained obscure. We have investigated this phenomenon in an in vitro system. A preparation of polyclonal immunoglobulin, human normal globulin (HNG), induced a change in the phenotype of immortalized porcine endothelial cells (IPEC) suggestive of accommodation; the cells became resistant to complement mediated lysis and displayed a reduced expression of surface VCAM and MHC class I. The accommodated phenotype only manifested after 72 hr incubation with HNG and was optimal after 120 hr. In an analysis of all the experiments performed, the development of resistance to complement mediated lysis appeared independent of the inducing dose of HNG. However, down-regulation of VCAM was only manifest when subsaturating doses were used. Our results suggest that IgG xenoreactive antibodies can mediate changes in porcine endothelial cell phenotype consistent with accommodation. The dependence on both time and dose of antibody applied might explain why accommodation has been difficult to achieve consistently in in vivo models of discordant xenotransplantation. By demonstrating a functional interaction between human VLA-4 and porcine VCAM, we speculate that the down-regulation in expression of VCAM on accommodated endothelium may have an important regulatory effect on traffic of inflammatory cells into xenografts. Our results have important implications for the development of strategies to promote accommodation of xenografts.