Nucleotides and nucleosides represent an important and ubiquitous class of molecules that interact with specific receptors, regulate a variety of activities within the liver, and play a role in the pathogenesis of hepatic fibrosis. Ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPPs) are ecto-enzymes that are located on the cell surface. NPP1, NPP2, and NPP3 (abbreviated as NPP1-3 hereafter) have been implicated in the hydrolysis of nucleotides; together with other ecto-nucleotidases, they control the events induced by extracellular nucleotides. We have identified and compared the expression of E-NPP family members in two different phenotypes of the mouse hepatic stellate cell line (GRX). In quiescent-like hepatic stellate cells (HSCs), E-NPP activity was significantly higher, NPP2 mRNA expression decreased and NPP3 mRNA increased. The differential NPP activity and expression in two phenotypes of GRX cells suggests that they are involved in the regulation of extracellular nucleotide metabolism in HSCs. However, the role of E-NPPs in the liver remains to be clarified.