The human anticoagulant factor, Protein C, is a plasma glycoprotein that has reported anti-ischaemic and anti-inflammatory properties. To explore potential mechanisms for these reported activities, we examined the effect of Protein C on the process of cell adhesion to vascular endothelial cells, which plays a critical role during inflammatory responses. We show that both human plasma-derived and human cell-produced recombinant Protein C inhibit E-selectin-mediated cell adhesion. This effect was not mediated through the serine protease activity of Protein C, but through its carbohydrates. Using oligosaccharides isolated from human cell-produced Protein C, we have defined a polylactosamine structural determinant that inhibits adhesion. This uncharged detenminant appears to be a more potent ligand for E-selectin than the sialylated Lewis X antigen. Our data suggest a potential mechanism for the reported anti-inflammatory effects of Protein C and describe a new ligand for selectin-mediated adhesion.