The additivity of DNA synthesis induced by hepatocyte growth factor/scatter factor (HGF/SF) and epidermal growth factor (EGF) was revealed in periportal hepatocytes (PPH), perivenous hepatocytes (PVH), and primary hepatocytes. Furthermore, additivity of the signal transduction pathway of HGF/SF and EGF was investigated (i.e., the activity of mitogen-activated protein kinase (MAPK) induced by HGF/SF and EGF), but it was not seen in PPH, PVH, or primary hepatocytes, although wortomannin, a PI 3-kinase inhibitor, abolished the additivity. The additivity of DNA synthesis induced by HGF/SF and EGF was not related to hepatocyte heterogeneity, but to a difference in the signal transduction pathway, probably another pathway that is different from the classical MAPK (MAPK/ERK1,2) path,