Angiotensin II (Ang II) is a crucial contributor to inflammatory processes involved in development and progression of atherosclerotic lesion. Toll-like receptor 4 (TLR4) signaling responsible for the initiation of inflammation also participates in pathogenesis of atherosclerosis. The protective effect of peroxisome proliferator-activated receptor alpha (PPARalpha) activators on atherosclerosis may be due to their impact on vascular inflammation, plaque instability and thrombosis. However, mechanisms underlying the inhibitory effects of PPARalpha activators on Ang II-induced vascular inflammation and the TLR4-dependent signaling pathway involved in vascular smooth muscle cells (VSMCs) remain unclear. The present study demonstrated that PPARalpha activator fenofibrate decreased Ang II-induced generation of pro-inflammatory mediators such as TLR4, MMP-9 and TNF-alpha, but enhanced production of anti-inflammatory molecules like PPARalpha and 6-keto-PGF(1alpha) both in vivo and in vitro. Meanwhile, treatment of VSMCs with the TLR4 inhibitor or TLR4 siRNA showed that the inhibitory effects of fenofibrate on Ang II-induced inflammatory responses in VSMCs were dependent on TLR4. Furthermore, fenofibrate depressed Ang II-induced inflammatory responses in VSMCs by intervening the downstream effector molecules of the TLR4-dependent signaling pathway, including interferon-gamma inducible protein 10 (IP-10), protein kinases C (PKC) and nuclear factor kappaB (NF-kappaB). Thus, these findings provide the evidence for beneficial effects of PPARalpha activator fenofibrate to counter-regulate vascular inflammation induced by Ang II. More importantly, anti-inflammatory action of fenofibrate via interfering with the TLR4-dependent signaling pathway (TLR4/IP-10/PKC/NF-kappaB) works in concert to protect against atherosclerosis.