Human protein C and activated protein C are shown to bind to endothelium specifically, selectively and saturably (Kd = 30 nM, 7000 sites per cell) in a Ca(2+)-dependent fashion. Expression cloning revealed a 1.3-kilobase pair cDNA that coded for a novel type 1 transmembrane glycoprotein capable of binding protein C. This protein appears to be a member of the CD1/major histocompatibility complex superfamily. Like thrombomodulin, the receptor involved in protein C activation, the endothelial cell protein C receptor function and message are both down-regulated by exposure of endothelium to tumor necrosis factor. Identification of endothelial cell protein C receptor as a member of the CD1/major histocompatibility complex superfamily provides insights into the role of protein C in regulating the inflammatory response.