Inflammatory processes, aside from cholesterol, play a central role in atherogenesis. Human C-reactive protein (huCRP) signals systemic inflammation and independently predicts future cardiovascular risk. Cholesterol-lowering statins reduce atherosclerosis and plasma huCRP levels. Evidence is sought for a direct anti-inflammatory statin effect in vivo, independent of effects on plasma cholesterol and atherogenesis. The effect of atorvastatin and simvastatin on huCRP expression was studied in nonatherosclerotic huCRP transgenic mice and compared with another class of hypolipidemic drugs, peroxisome proliferator-activated receptor-alpha (PPARα) activators, notably fenofibrate and Wy14643. Like statins, PPARα activators combine antiatherosclerotic properties with huCRP-lowering effects. Dietary treatment with statins or PPARα activators decreased basal and interleukin-1β (IL-1β)-induced plasma huCRP levels independently of cholesterol lowering. These direct anti-inflammatory in vivo effects occurred at the transcriptional level and could be confirmed in cultured human liver slices and in human hepatoma cells transiently transfected with a huCRP promoter-driven luciferase reporter. A molecular rationale for the suppression of IL-1-induced huCRP transcription is provided by showing that statins and PPARα activators up-regulate IκBα expression. This results in a reduced nuclear translocation of p50-nuclear factor κ B (NFκB) and thereby decreased amounts of nuclear p50-HFκB∼CCAAT/enhancer binding protein beta (C/EBPβ) complexes, which determine the huCRP transcription rate. Our results provide conclusive evidence for a direct suppressive effect of statins and PPARα activators on huCRP expression independent of cholesterol lowering and atherogenesis. © 2004 by The American Society of Hematology.