In fibroblasts, thrombin induces collagen deposition through activation of a G‐protein–coupled receptor, proteinase‐activated receptor 1 (PAR₁). In the current study, we examined whether PAR₁ antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (BDL). The current results demonstrated that HSCs express PAR₁, as well as proteinase‐activated receptors 2 (PAR₂) and 4 (PAR₄), and that all three PARs were up‐regulated in response to exposure to growth factor in vitro. Exposure to thrombin and to SFLLRN‐(SF)‐NH₂, a PAR₁ agonist, and GYPGKF (GY)‐NH₂, a PAR₄ agonist, triggered HSC proliferation and contraction, as well as monocyte chemotactic protein‐1 (MCP‐1) production and collagen I synthesis and release. These effects were inhibited by the PAR₁ antagonist. Administration of this antagonist, 1.5 mg/kg/d, to BDL rats reduced liver type I collagen messenger RNA (mRNA) expression and surface collagen by 63%, as measured by quantitative morphometric analysis. Similarly, hepatic and urinary excretion of hydroxyproline was reduced significantly by the PAR₁ antagonist. In conclusion, PAR_s regulates HSC activity; development of PAR antagonists might be a feasible therapeutic strategy for protecting against fibrosis in patients with chronic liver diseases. (HEPATOLOGY 2004;39:365–375.)