Platelet activation is believed to play an important role in the triggering of thrombosis of human blood by pig islets. We used a transgenic mouse model to investigate whether overexpression of CD39 (ecto nucleoside triphosphate diphosphohydrolase 1 [ENTPD1], EC 3.6.1.5), an ectonucleotidase that degrades the platelet agonists ATP, could interfere with this process. Islets isolated from CD39 transgenic mice showed 2.4-fold higher NTPDase activity than wild-type controls. When incubated with human blood, these islets significantly delayed clotting time compared to wild type islets (7.9 +/- 0.89 min versus 4.3 +/- 0.77 min, P = 0.007). Importantly, expression of human CD39 in the islets of transgenic mice had no deleterious effect on glucose metabolism. These results suggest that transgenic expression of human CD39 does not interfere with islet function and may be a useful strategy to inhibit thrombosis induced by intraportal administration of islet xenografts.