Hepatocyte growth factor (HGF) is known to induce the dispersion of epithelial cells, as scatter factor. On the other hand, cadherins play a crucial role in connecting cells together. Two groups of cadherins are involved in epithelial cell adhesion, those locating in adherens junctions (AJ) and in desmosomes. Here, we examined the effect of HGF on the function of these cadherins in keratinocyte cell lines F and 308R, which expressed E- and P-cadherin in AJ (referred to as AJ cadherins) and desmoplakin in desmosomes. In the presence of HGF, these cells spread more extensively than in control cultures and their associations apparently loosened. However, they maintained cell-cell contacts where cadherins and desmoplakin concentrated, although the level of the concentration was reduced by HGF treatment. When antibodies to E- and P-cadherins were added to cultures of these cells without HGF, AJ cadherins were redistributed into non-junctional areas of the cells, but desmoplakin still localized at cell-cell boundaries. When HGF was added together with anti-AJ cadherin antibodies to the cultures, cell-cell contacts were now disrupted. In these cultures, not only AJ cadherins but also desmoplakin were lost at cell-cell contact sites, indicating that HGF can disrupt desmosomal cell-cell adhesion when AJ cadherins are inactive. These results suggest that, although HGF cannot block cadherin-mediated cell-cell adhesion when the entire cadherin system is intact, it might modulate the activities of cadherins, especially, of desmosomal cadherins.