Vasoactive factors that regulate splanchnic hemodynamics include nitric oxide, catecholamines, and possibly extracellular nucleosides/nucleotides (adenosine, ATP). CD39/NTPDase1 is the major vascular ectonucleotidase that hydrolyzes extracellular nucleotides. CD39 activity may be modulated by vascular injury, inflammation and altered oxygen tension. Altered Cd39 expression by the murine hepatosplanchnic vasculature may impact hemodynamics and portal hypertension (PHT) in vivo. We noted that basal portal pressures (PP) were comparable in wild type and Cd39 null mice (n=9). ATP infusions resulted in increments in PP in wild-type mice but in contrast, this significantly decreased in Cd39-null mice (n=9) post-ATP in a nitric oxide dependent manner. We then studied Cd39/NTPDase1 deletion in the regulation of portal hemodynamics, vascular integrity and intestinal permeability in a murine model of PHT. Partial portal vein ligation (PPVL) was performed in Cd39-null (n=44) and wild-type (n=23) mice. Sequential measurements obtained after PPVL were indicative of comparable levels of portal hypertension (ranges 14-29 mmHg) in both groups. There was one death in the wild-type group; and eight in the Cd39-null group from intestinal bleeding (P=0.024). Circulatory stasis in the absence of overt portal vein thrombosis, portal congestion, intestinal hemorrhage, and increased permeability were evident in all surviving Cd39-null mice. Deletion of Cd39 results in deleterious outcomes post-PPVL that are associated with significant microcirculatory derangements, major intestinal congestion with hemorrhage mimicking acute mesenteric occlusion. Absent Cd39/NTPDase1 and decreased generation of adenosine in the splanchnic circulation causes heightened vascular permeability and gastrointestinal hemorrhage in PPVL.