Background and objectives: β3 Integrin may play a role in the process of acute rejection by increasing leukocyte adhesion to the endothelium, cytotoxic T lymphocyte activation, and platelet aggregation. Design, setting, participants, & measurements: For investigation of the role of β3 integrin in the pathogenesis of acute rejection, this study examined the surface expression of β3 integrin on leukocyte subsets and analyzed a common single-nucleotide polymorphism in exon 2 of the gene encoding the β3 subunit that generates two β3 integrin isoforms, termed PlA1 and PlA2. PlA genotype was determined in blood samples from 445 renal allograft recipients at two centers. Patients were then grouped by PlA genotype, and clinical outcomes as recorded in a preexisting database were analyzed. Results: Although almost all monocytes express β3 integrin, its expression was also found on all leukocyte subsets, including T, B, and NK cells. The percentage of patients who experienced acute rejection was noted to be significantly higher in those with PlA1/PlA1 (TT) genotype versus patients with the PlA1/PlA2 or PlA2/PlA2 (CT or CC) genotypes (33% for TT versus 20% for CT or CC). In a multivariate analysis, the PlA1/PlA1 (TT) genotype remained significantly associated with acute rejection. Patients with PlA1/PlA1 (TT) genotype also exhibited a higher number of acute rejection episodes per patient. Conclusions: The PlA1/PlA1 (TT) genotype is associated with an increased incidence of acute renal allograft rejection in humans, supporting a role for β3 integrin in the pathophysiology of acute rejection. Copyright © 2007 by the American Society of Nephrology.