Liver fibrosis results from chronic tissue damage and excessive regeneration with accumulation of extracellular matrix proteins; it is a precursor of liver cirrhosis and hepatocellular carcinoma. Liver fibrosis treatments are primarily directed at inflammation, with few options to combat fibrogenesis. Pirfenidone is a drug approved for idiopathic pulmonary fibrosis and this study was focused on anti-fibrotic and anti-cancer potential of pirfenidone in the liver of male B6C3F1/J mice. In a dose-finding study, mice were treated with CCl4 (0.2 ml/kg ip, 2 × wk for 4 weeks) while on a pirfenidone-containing (0–600 mg/kg) diet. Pirfenidone at doses of 300 and 600 mg/kg had significant anti-fibrotic (collagen) and anti-inflammatory (serum transaminases and “ballooning” hepatocyte) effects. In a sub-chronic study (14 weeks), mice received CCl4 while on pirfenidone (300 mg/kg) diet. Pirfenidone significantly reduced collagen deposition, but had little effect of inflammation and injury. In an initiation-promotion cancer study with N-nitrosodiethylamine and CCl4, pirfenidone (300 mg/kg) did not affect incidence, size, or multiplicity of liver tumors. Overall, we conclude that while pirfenidone exhibits strong anti-fibrotic effects in early stage liver fibrosis, it is less effective in advanced liver fibrosis and was not protective in an initiation-promotion liver cancer.