Chronic inflammation is an important trigger of liver fibrogenesis. Although well described, inflammatory pathways have received little attention as therapeutic targets for chronic liver diseases. IL-37 has proven to exert broad-spectrum anti-inflammatory effects in vitro and in vivo. Furthermore, IL-37 interferes with the TGF-β signaling pathway by interaction with Smad3. Since TGF-β is a core cytokine involved in liver fibrogenesis we hypothesized that IL-37 modulates liver fibrosis by functional interaction with the TGF-β signaling pathway. Here we show that transgene expression of IL-37 in mice is associated with prolonged survival, reduced hepatic damage and early fibrosis markers as well as less histologically proven liver fibrosis after bile duct ligation (BDL). IL-37tg mice were also protected against CCl4-induced liver inflammation. In addition, colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout mice expressing IL-37. Spontaneous as well as LPS/TGF-β-induced cytokine release and pro-fibrogenic gene expression was lower in hepatic stellate and Kupffer cells isolated from IL- 37tg mice and IL-37 overexpressing, IL-1β- or LPS-stimulated human LX-2 stellate, RAW264.7 and A549 cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, in LX2 cells or murine HSCs. We therefore conclude that predominantly intracellular IL-37 down-regulates pathways of liver inflammation and fibrosis. In addition to our functional studies we show that IL-37 expression is increased in pediatric autoinflammatory liver diseases and correlates with fibrosis, serum transaminases, alkaline phosphatase and IgG. In addition, we demonstrate in a large cohort of adults with chronic liver diseases elevated serum IL-37 levels correlating with clinical markers of liver fibrosis. In summary, our results indicate that IL-37 may represent a novel target to modulate the clinical course of chronic liver diseases.