Leptin signaling is involved in T‐cell polarization and is required for profibrotic function of hepatic stellate cells (HSCs). Leptin‐deficient ob/ob mice do not develop liver fibrosis despite the presence of severe long‐standing steatohepatitis. Here, we blocked leptin signaling with our recently generated mouse leptin antagonist (MLA), and examined the effects on chronic liver fibrosis in vivo using the chronic thioacetamide (TAA) fibrosis model, and in vitro using freshly‐isolated primary HSCs. In the chronic TAA fibrosis model, leptin administration was associated with significantly enhanced liver disease and a 100% 5‐week to 8‐week mortality rate, while administration or coadministration of MLA markedly improved survival, attenuated liver fibrosis, and reduced interferon γ (IFN‐γ) levels. No significant changes in weight, serum cholesterol, or triglycerides were noted. In vitro administration of rat leptin antagonist (RLA), either alone or with leptin, to rat primary HSCs reduced leptin‐stimulated effects such as increased expression of α‐smooth muscle actin (α‐SMA), and activation of α1 procollagen promoter. Conclusion: Inhibition of leptin‐enhanced hepatic fibrosis may hold promise as a future antifibrotic therapeutic modality. (HEPATOLOGY 2009;49:278‐286.)