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-α (PPARα) agonists attenuate the IL-6 induction of acute-phase response gene expression in vitro and in vivo. In the current work, we found a PPARα-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 PPARα activation in liver. Direct involvement of hepatic PPARα was demonstrated using a liver-restricted expression of PPARα in mice. IL-1- or IL-6-mediated acute-phase response was inhibited by fenofibrate treatment in liver-specific PPARα-expressing mice but not in PPARα-deficient mice. In addition, we demonstrated that PPARα exerts a general control of the acute-phase response by using an inflammation/infection model of lipopolysaccharide. In such a context, liver-specific PPARα-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, PPARα behaves as a modulator of systemic inflammation and of the associated vascular response.