The importance of inflammation in initiating the sequence of events that lead to liver fibrosis is increasingly recognized. In this study, we tested the effects of SC‐236, a selective cyclooxygenase (COX)‐2 inhibitor, in rats with carbon tetrachloride (CCl₄)‐induced liver fibrosis. Livers from CCl₄‐treated rats showed increased COX‐2 expression and 15‐deoxy‐prostaglandin (PG)J₂ (15d‐PGJ₂) formation, as well as decreased peroxisome proliferator‐activated receptor (PPAR)γ expression. In these animals, SC‐236 reduced liver fibrosis as revealed by histological analysis and by a reduction in hepatic hydroxyproline levels, metalloproteinase‐2 activity, and α‐smooth muscle actin expression. Interestingly, SC‐236 normalized 15d‐PGJ₂ levels and restored PPARγ expression in the liver of CCl₄‐treated rats. In isolated hepatic stellate cells (HSCs)—the major player in liver fibrogenesis—and Kupffer cells—the cell type primarily responsible for increased hepatic COX‐2—SC‐236 exhibited remarkable pro‐apoptotic and growth inhibitory properties. Of interest, SC‐236 decreased HSC viability to a similar extent than the PPARγ ligand rosiglitazone. Moreover, SC‐236 significantly induced PPARγ expression in HSCs and acted as a potent PPARγ agonist in a luciferase‐reporter trans‐activation assay. These data indicate that, by mechanisms involving non‐parenchymal cell apoptosis and PPARγ activation, the selective COX‐2 inhibitor SC‐236 might have therapeutic potential for prevention of liver fibrosis.