The Fenofibrate Intervention and Event Lowering in Diabetes study demonstrated that treatment with fenofibrate in individuals with type 2 diabetes mellitus not only reduced nonfatal coronary events but also diminished the need for laser treatment of diabetic retinopathy and delayed the progression of diabetic nephropathy. However, the mechanism by which fenofibrate may have altered the microvasculature remains unclear. We thus investigated the effect of fenofibrate on human glomerular microvascular endothelial cells (HGMEC). Treatment of HGMEC with fenofibrate resulted in transient activation of adenosine monophosphate–activated protein kinase (AMPK), thereby inducing the phosphorylation of Akt and endothelial nitric oxide synthase, leading to nitric oxide production. We compared AMPK activation induced by bezafibrate and WY14643 with that induced by fenofibrate in HGMEC as well as HepG2 cells. Only fenofibrate activated AMPK in HGMEC. Fenofibrate also inhibited nuclear factor–κB activation by advanced glycation end-products, thereby suppressing the expression of various adhesion molecule genes in HGMEC. Suppression of fenofibrate-induced inhibition of nuclear factor–κB activation was observed in cells treated with AMPK small interfering RNA or compound C. Furthermore, fenofibrate was observed to significantly suppress apoptosis of HGMEC in hyperglycemic culture medium. Treatment with compound C or Nw-nitro-L-arginine methyl ester (L-NAME) abolished the suppressive effect of fenofibrate on HGMEC apoptosis. Our findings suggest that fenofibrate might exert a protective effect on the microvasculature by suppressing inflammation and apoptosis through AMPK activation beyond its lipid-lowering actions.