The remarkable regenerative potential of the liver is well known. Recent investigations have shown that this regenerative response is impaired in mouse models of fatty liver disease. Other studies demonstrate that mice engineered for liver-specific overexpression of the peroxisome proliferator activated receptor gamma (PPAR) develop significant hepatic steatosis. These observations suggest that precise regulation of hepatic PPAR activity may be essential for normal liver regeneration. To test this hypothesis, we analyzed the effects of PPAR-activating thiazolidinediones on liver regeneration in the rodent partial hepatectomy model. Thiazolidinediones with different PPAR-activating potencies were administered to mice, and those mice were subjected to partial hepatectomy and analyzed for resulting effects on hepatocellular proliferation and signaling pathways important during normal liver regeneration. The results showed that thiazolidinediones suppress liver regeneration with efficacies that correlate with their relative PPAR-activating potencies. These studies provide the first evidence linking regulation of PPAR activity and the hepatic regenerative response.--Turmelle, Y. P., Shikapwashya, O., Tu, S., Hruz, P. W., Yan, Q., Rudnick, D. A. Rosiglitazone inhibits mouse liver regeneration.