The acute phase response is characterized by the modulation of liver expression of many proteins involved in a diversity of biological functions. Among them, some are associated with the pathology of atherosclerosis. We previously found that Peroxisome Proliferator-Activated Receptor alpha (PPAR) agonists attenuate the IL-6 induction of acute phase response gene expression in vitro and in vivo. In the current work, we found a PPAR-dependent regulation of hepatic acute phase response stimulated by IL-1. We also found that IL-1-stimulated expression of secondary wave cytokines such as IL-6 is prevented upon PPAR activation in liver. Direct involvement of hepatic PPAR was demonstrated using a liver-restricted expression of PPAR in mice. IL-1 or IL-6 mediated acute phase response was inhibited by fenofibrate treatment in liver-specific PPAR expressing mice but not in PPAR-deficient mice. In addition, we demonstrated that PPAR exerts a general control of the APR by using an inflammation/infection model of LPS. In such a context, liver-specific PPAR expressing mice displayed lower circulating levels of TNF, IL-1 and IL-6 cytokines. We found a distal repercussion of this lowering at the vascular wall level as illustrated by a decreased expression of adhesion molecules in aorta. In conclusion, we demonstrated that through a specific liver action, PPAR behaves as a modulator of systemic inflammation and of the associated vascular response.