PURPOSE: Leukocyte endothelial interactions are a key feature of ocular angiogenesis but also play a role in nonproliferative vascular alterations as are found in early diabetes or uveitis. The adhesion of leukocytes to endothelial cells during inflammation is a multistep process that involves leukocyte rolling, adhesion, and extravasation mediated by selectins, cell adhesion molecules (CAMs), integrins, and chemokines. Heparan sulfate (HS) is known to bind to and modify the function of these molecules under physiological conditions. In this study, the role of the HS proteoglycan syndecan-1 in mediating leukocyte-endothelial interactions in the ocular vasculature was investigated. METHODS: Mice carrying a deletion in the gene encoding the cell surface HS proteoglycan syndecan-1 (sdc1) were used to study the interactions of leukocytes and endothelial cells in vivo, using a perfusion technique with FITC-coupled ConA and intravital microscopy. RESULTS: In a retina perfusion model, Sdc1(-/-) mice showed increased leukocyte adhesion that was largely attributable to the leukocytes. Intravital microscopy studies revealed a dramatic increase in adhesion after tumor necrosis factor (TNF)-alpha treatment of sdc1(-/-) mice compared with similarly treated wild-type mice. The higher degree of leukocyte adhesion may account for the increase in inflammation-mediated corneal angiogenesis observed in sdc1(-/-) mice. CONCLUSIONS: The results indicate a role for syndecan-1 as a negative regulator of leukocyte-mediated inflammatory responses. Thus, syndecan-1 could have use as a target for prevention of pathologic leukocyte-endothelial interactions in angiogenesis and inflammation.