The purpose of this study was to investigate the possible mechanisms of Crocus sativus saffron against diethylnitrosamine (DEN)-induced liver cancer in rats. Administration of Crocus sativus saffron at a dose of 300 mg/kg/day was started 2 weeks prior to the DEN and CCL4 injection and was continued for 42 days. Crocus sativus saffron significantly reduced the DEN-induced increase in the number and the incidence of hepatic dyschromatic nodules, saffron restored the superoxide dismutase, catalase and malondialdehyde levels and increased the expression of active caspase 3 and inhibited the formation of MMP9