Fluid shear stress has been shown to modulate various endothelial functions. We selected a shear stress-specific clone, identified as collagen XII, from a bovine aortic endothelial cell (BAEC) cDNA library. We confirmed that shear stress induces collagen XII expression at both the mRNA and protein levels in cultured BAECs and human umbilical vein ECs (HUVECs) by stimulating transcription. When HUVECs were exposed to shear stress, they secreted collagen XII protein and it was deposited underneath them. Strong expression of collagen XII was found in the intima of human aortic wall lacking atherosclerotic lesions, whereas weak expression was seen in the intima of atherosclerotic plagues. Furthermore, the downstream portion of atherosclerotic plaques showed apparently weak collagen XII expression compared with the upstream portion. These results suggest that collagen XII expression induced by fluid shear stress may play a role in stabilizing the vascular structure and preventing the formation of atherosclerotic lesions.