Hepatocyte growth factor (HGF)/scatter factor (SF) is a cytokine exerting a wide range of biological functions on many cell types, including vascular endothelial cells. HGF/SF increases migration, motility, and dissociation of human umbilical vascular endothelial cells (HUVECs). This study demonstrated that such action of HGF/SF on HUVECs was achieved by regulation of the endothelial cell-specific cadherin, vascular endothelial (VE)-cadherin. HGF/SF induced a time-dependent reduction of VE-cadherin protein from HUVECs as shown by Western blotting and immunocytochemistry, accompanied by an increase in the migration of HUVECs. The change of VE-cadherin appeared at the mRNA level, as demonstrated by reverse transcription-PCR, with a decrease in the VE-cadherin signal. These results show, for the first time, that HGF/SF targets the endothelial cell-specific adhesion molecule VE-cadherin.