Connective tissue growth factor (CCN2) is a matricellular protein that is up‐regulated in many fibrotic disorders and coexpressed with transforming growth factor β. CCN2 promotes fibrogenesis and survival in activated hepatic stellate cells, and injured or fibrotic liver contains up‐regulated levels of CCN2 that are produced by a variety of different cell types, including hepatocytes. To investigate CCN2 action in vivo, transgenic FVB mice were created in which the human CCN2 gene was placed under the control of the albumin enhancer promoter to elevate hepatocyte CCN2 levels. Production of human CCN2 (hCCN2) messenger RNA and elevated CCN2 protein levels was demonstrated in transgenic livers, whereas levels of endogenous mouse CCN2 were comparable between transgenic and wild‐type mice. Liver histology and liver function tests were unaffected in transgenic animals. However, after chronic administration of CCl₄, α‐smooth muscle actin (α‐SMA)–expressing cells and collagen deposition were increased as a function of the dosage of the hCCN2 transgene (hccn2^+/+ > hccn2^+/− > hccn2^−/−). Moreover, CCl₄‐induced serum hyaluronic acid, hepatic tissue levels of α‐SMA or acid‐soluble collagen, and messenger RNA expression of α‐SMA, collagen α1 (I), matrix metalloprotease‐2, or tissue inhibitor of metalloprotease‐1 were greater in transgenic mice than in wild‐type mice. Transgenic mice also exhibited enhanced hepatic deposition of collagen 2 weeks after bile duct ligation. Conclusion: Production of elevated CCN2 levels in hepatocytes of transgenic mice in vivo does not cause hepatic injury or fibrosis per se but renders the livers more susceptible to the injurious actions of other fibrotic stimuli. These studies support a central role of CCN2 in hepatic fibrosis and demonstrate a role of the microenvironment in regulating the profibrotic action of CCN2. (HEPATOLOGY 2009.)