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The inflammatory response to liver injury plays an important role in the onset of liver fibrosis, which may ultimately lead to liver failure. The attenuation of inflammation and hepatocyte rescue are, therefore, of the utmost importance for recovery. Mesenchymal stromal cells (MSCs) from adult bone marrow have been shown to rescue hepatocyte function. Here we explore a more plentiful source of neonatal MSCs: human umbilical cord perivascular cells (HUCPVCs). We cocultured HUCPVCs or bone marrow–derived mesenchymal stromal cells (BM-MSCs) with rat hepatocytes or human peripheral blood mononuclear cells in order to identify their effects on hepatocyte functionality and the proliferation of phytohemagglutinin-stimulated peripheral blood mononuclear cells (phaPBMCs). The expression of hepatotrophic factors by both types of MSCs in the presence of hepatocytes and the functional implications of blocking putative MSC anti-inflammatory factors were compared. Both types of MSCs improved albumin secretion, ureagenesis, hepatospecific gene expression, cytochrome P450 (CYP) activity, and functional hepatocyte mass maintenance. However, although HUCPVCs had an improved effect on the maintenance of ureagenesis, BM-MSCs had a strong effect on hepatocyte CYP activity. Additionally, each MSC type differentially expressed putative hepatotrophic factors, whereas phaPBMC proliferation was significantly decreased. Indoleamine 2,3-dioxygenase (IDO) was the main immunosuppressive mechanism used by both types of MSCs, but HUCPVCs exhibited higher expression of programmed death 1 ligands. However, the functional significance of the difference in anti-inflammatory factor expression still remains to be elucidated. Thus, both MSC types can serve as hepatocyte stromal cells and mitigate inflammation with IDO, but they present differences in the manner in which they affect hepatocytes and in the expression of both hepatotrophic and anti-inflammatory factors. Liver Transpl 18:1384–1394, 2012. © 2012 AASLD.