Previously, we have suggested that liver cell proliferation induced by certain mitogens is dependent on their binding and activation of nuclear receptors of the steroid/thyroid superfamily. More recently, it was shown that absence of the nuclear receptors peroxisome proliferator–activated receptor-α (PPARα) and constitutive androstane receptor (CAR) completely abolishes the proliferative response of hepatocytes to the mitogenic stimulus exerted by their specific ligands, peroxisome proliferators (PPs) and 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), respectively. Here we show that deletion of the PPARα gene accelerates and enhances the proliferative response evoked by the xenobiotic 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a powerful mouse-liver mitogen and a ligand of the nuclear receptor CAR. Indeed, the number of hepatocytes entering S phase 24 hours after mitogen treatment was much greater in PPARα−/− mice compared with that of wild type mice (labeling indices 21.4% and 7.5%, respectively). Labeling index of hepatocytes from PPARα−/− mice was found to be higher than that of wild type mice up to 36 hours after treatment, indicating that lack of PPARα not only accelerated but also enhanced the overall proliferative response of the liver. The accelerated entry into S phase observed in hepatocytes from PPARα−/− mice was associated with a very rapid induction of cyclin D1. No major differences between TCPOBOP-treated PPARα−/− and wild type mice were observed in the expression of the 2 inhibitors of cyclin/CDKs complexes, p27 and p21. The results suggest that PPARα may play a role in modulating CAR-signaling pathways in the cell, in particular those leading to hepatocyte proliferation.