Atherosclerotic cardiovascular disease is the number one cause of death for adults in the Western society. Plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activators, has been implicated in both thrombogenesis and atherogenesis. Previous studies demonstrated that copper-oxidized low density lipoprotein (C-oLDL) stimulated production of PAI-1 in vascular endothelial cells (ECs). The present study examined the involvement of lectin-like oxidized LDL receptor-1 (LOX-1) and Ras/Raf-1/ERK-1/2 pathway in the upregulation of PAI-1 in cultured ECs induced by oxidized LDLs. The results demonstrated that C-oLDL or FeSO4-oxidized LDL (F-oLDL) increased the expression of PAI-1, LOX-1 or H-Ras in human umbilical vein ECs (HUVECs) or coronary artery ECs (HCAECs). LOX-1 blocking antibody, Ras farnesylation inhibitor (FTI-277) or small interference RNA against H-Ras significantly reduced C-oLDL or LDL-induced expression of H-Ras and PAI-1 in ECs. Incubation with C-oLDL or F-oLDL increased the phosphorylation of Raf-1 and ERK1/2 in ECs compared to LDL or vehicle. Treatment with Raf-1 inhibitor blocked Raf-1 phosphorylation and the elevation of PAI-1 mRNA level in ECs induced by C-oLDL or LDL. Treatment with PD98059, an ERK-1/2 inhibitor, significantly inhibited the effects of C-oLDL or LDL on ERK-1/2 phosphorylation or PAI-1 expression. The results suggest that LOX-1, H-Ras and Raf-1/ERK-1/2 are involved in PAI-1 expression induced by oxidized LDLs or LDL in cultured ECs.