Mice subjected to partial hepatectomy (PH) develop hypoglycemia, followed by increased systemic lipolysis and hepatic fat accumulation, prior to onset of hepatocellular proliferation. Strategies that disrupt these metabolic events inhibit regeneration. These observations suggest that alterations in metabolism in response to hepatic insufficiency promote liver regeneration. Hepatic expression of the peroxisome proliferator-activated receptor gamma (PPARγ) influences fat accumulation in the liver. Therefore, the studies reported here were undertaken to assess the effects of disruption of hepatic PPARγ expression on hepatic fat accumulation and hepatocellular proliferation during liver regeneration. The results showed that liver regeneration was not suppressed, but rather modestly augmented in liver-specific PPARγ null mice maintained on a normal diet. These animals also exhibited accelerated hepatic cyclin D1 expression. Because hepatic PPARγ expression is increased in experimental models of fatty liver disease in which liver regeneration is impaired, regeneration in liver-specific PPARγ null mice with chronic hepatic steatosis was also examined. In contrast to the results described above, disruption of hepatic PPARγ expression in mice with diet-induced hepatic steatosis resulted in significant suppression of hepatic regeneration. Conclusion: The metabolic and hepatocellular proliferative responses to PH are modestly augmented in liver-specific PPARγ null mice, thus providing additional support for a metabolic model of liver regeneration. Furthermore, regeneration is significantly impaired in liver-specific PPARγ null mice in the setting of diet-induced chronic steatosis, suggesting that pharmacological strategies to augment hepatic PPARγ activity might improve regeneration of the fatty liver.