Extracellular nucleotide stimulation of purinergic/pyrimidinergic type-2 (P2) receptors are components of platelet, endothelial cell (EC), and leukocyte activation that culminate in vascular thrombosis and inflammation in vivo. CD39, the prototype nucleoside triphosphate diphosphohydrolase (or NTPDase-1), is highly expressed on quiescent endothelium, monocytes, and activated lymphocytes and therefore could influence these pathways. The potential of NTPDase-1 to regulate P2-receptor function in the vasculature has been established by our generation of cd39-null mice. These mice exhibit a prothrombotic vascular phenotype ascribed to overexpression of tissue factor by endothelial cells following aberrant P2-(and potentially adenosine 2a/3) receptor activation. Mutant mice also show perturbations in hemostasis, secondary to platelet P2Y1-receptor desensitization. In addition, administration of soluble NTPDase and/or induction of CD39 overexpression by adenoviral vectors consistently result in amelioration of vascular injury in several animal models tested. CD39 is also the major NTPDase expressed by monocyte-macrophages (Mo). Upregulation of tissue factor expression by Mo in vitro and alterations in splenic populations in vivo have been observed in cd39-null mice. Paradoxical inhibition of integrin-mediated adhesion and transendothelial migration of cd39-null Mo are also related to aberrant P2-receptor activation and have also been observed in vitro and in vivo. Overexpression of CD39 following infection with recombinant adenoviral vectors also blocks LPS-induced ATP secretion and inhibits IL-1 release in vitro. These studies confirm a role for CD39 in the differential regulation of P2-receptor activity and function in platelets, vascular, and immune cells. Drug Dev. Res. 53:193-207, 2001.