Liver regeneration after partial hepatectomy (PH) involves several signaling mechanisms including activation of the small GTPases Ras and RhoA in response to mitogens leading to DNA synthesis and cell proliferation. Peroxisome proliferator-activated receptor- (PPAR) regulates the expression of several key enzymes in isoprenoid synthesis, which are key events for membrane association of Ras and RhoA. Thus the role of PPAR in cell proliferation after PH was tested. After PH, an increase in PPAR DNA binding was observed in wild-type mice, correlating with an increase in the PPAR-regulated enzyme acyl-CoA oxidase. In addition, the PPAR-regulated genes farnesyl pyrophosphate synthase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase were significantly increased in wild-type mice. However, these increases were not observed in PPAR knockout (PPAR /) mice. The peak in DNA synthesis observed 42 h after PH was reduced by ~60% in PPAR / mice, despite increases in TNF- and IL-1. Also, under these conditions, membrane association of Ras was high in wild-type mice after PH but was impaired in PPAR / mice. Accordingly, Ras was significantly elevated in the cytosol in PPAR / mice. This observation correlated with lower levels of active GTP-bound Ras after PH in PPAR / mice compared with wild-type mice. Similar observations were made for RhoA. Moreover, deletion of PPAR blunted the activation of cyclin-dependent kinase (cdk)2/cyclin E and cdk4/cyclin D complexes. Collectively, these results support the hypothesis that PPAR is necessary for cell cycle progression in regenerating mouse liver via mechanisms involving prenylation of small GTPases Ras and RhoA.