BACKGROUND/AIMS: In most cases infection with hepatitis C results in chronic infection as a consequence of viral subversion and failed anti-viral immune responses. The suggestion that dendritic cells are defective in chronic HCV infection led us to investigate the phenotype and function of liver-derived myeloid (mDC) and plasmacytoid (pDC) dendritic cells in patients with chronic HCV infection. METHODS: Liver DCs were isolated without expansion in cytokines from human liver allowing us to study unmanipulated tissue-resident DCs ex vivo. RESULTS: Compared with mDCs isolated from non-infected inflamed liver mDCs from HCV-infected liver (a) demonstrated higher expression of MHC class II, CD86 and CD123, (b) were more efficient stimulators of allogeneic T-cells and (c) secreted less IL-10. Reduced IL-10 secretion may be a factor in the enhanced functional properties of mDCs from HCV infected liver because antibody depletion of IL-10 enhanced the ability of mDCs from non-infected liver to stimulate T-cells. In contrast, pDCs were present at lower frequencies in HCV-infected liver and expressed higher levels of the regulatory receptor BDCA-2. CONCLUSIONS: In HCV-infected liver the combination of enhanced mDC function and a reduced number of pDCs may contribute to viral persistence in the face of persistent inflammation.