Nonalcoholic fatty liver disease (NAFLD) is a potentially progressive liver disease that culminates in cirrhosis. Cirrhosis occurs more often in individuals with nonalcoholic steatohepatitis (NASH) than in those with steatosis (nonalcoholic fatty liver [NAFL]). The difference between NAFL and NASH is the extent of hepatocyte apoptosis, which is more extensive in NASH. Because phagocytosis of apoptotic cells activates hepatic stellate cells (HSCs), we examined the hypothesis that a pan‐caspase inhibitor, VX‐166, would reduce progression of fibrosis in a mouse model of NASH. Male db/db mice were fed methionine/choline‐deficient (MCD) diets to induce NASH and liver fibrosis. Mice were gavaged once daily with either the pan‐caspase inhibitor VX‐166 (6 mg/kg/d; Vertex, Abingdon, UK) or vehicle only and sacrificed at 4 or 8 weeks. Treatment with an MCD diet increased alanine aminotransferase (ALT), caspase‐3 activity, terminal deoxynucleotidyl transferase–mediated dUTP nick‐end labeling (TUNEL)‐positive cells, NASH, and fibrosis. Treatment of MCD‐fed mice with VX‐166 decreased active caspase‐3, TUNEL‐positive cells, and triglyceride content (P < 0.05). However, ALT levels were similar in VX‐166–treated mice and vehicle‐treated controls. Histological findings also confirmed that both groups had comparable liver injury (NAFLD activity score ≥6). Nevertheless, VX‐166–treated MCD‐fed mice demonstrated decreased α‐smooth muscle actin expression (4 weeks, P < 0.05; 8 weeks, P < 0.005) and had reduced hepatic levels of collagen 1α1 messenger RNA (8 weeks, P < 0.05). Hydroxyproline content and Sirius red staining of VX‐166–treated livers confirmed decreases in fibrosis. Conclusion: Inhibiting hepatic apoptosis suppresses the development of fibrosis in mice with NASH. Beneficial effects on liver fibrosis were associated with reductions in hepatic steatosis, but occurred without obvious improvement in liver injury. These findings are consistent with evidence that apoptosis triggers HSC activation and liver fibrosis and suggest that caspase inhibitors may be useful as an antifibrotic NASH therapy. (HEPATOLOGY 2009.)