Thrombin inhibition protects against liver fibrosis. However, it is not known whether thrombin profibrogenic effect is due to effects on blood coagulation or to signaling via protease-activated receptors (PAR). We took advantage of the lack of blood coagulation defects in PAR-1 knock-out mice. Acute CCl4 toxicity was similar in wild-type (WT), PAR-1^-/- and PAR-1^+/- mice as judged by aminotransferases levels, area of liver necrosis, and liver peroxidation measured by Fourier transformed infrared spectroscopy. Fifteen mice/group received CCl₄ or its solvent for 6 weeks (300µl/kg, 3 times a week). Fibrosis area was increased ten-fold by CCl₄ treatment in WT mice. PAR-1 deficiency protected against fibrosis, with a 36% and 56% decrease in PAR-1^+/- and PAR-1^-/- mice, respectively (p<0.001). Similar results were obtained for the area of activated fibrogenic cells (64% and 79% decrease in PAR-1^+/- and PAR-1^-/- mice, respectively, p<0.001). These findings were corroborated by measurements of type I collagen, matrix metalloproteinase-2 and PDGF-R mRNA levels. There was also a significant decrease in T lymphocyte infiltration in PAR-1-deficient mice. Altogether, these results suggest that thrombin pro-fibrogenic effects are independent of effects on blood coagulation, but are instead due to direct effects on fibrogenic cells and possibly on T lymphocytes.