Regeneration of liver tissue in man after submassive necrosis is reflected by replicating features in hepatocytes, and by a remarkably increased number of bile duct structures that are thought to transdifferentiate into true functioning hepatocytes. Similar to the bile ductule-related "oval cells" in rats, human bile ductular cells may therefore serve as "facultative stem cells" that become activated when hepatocyte regeneration is insufficient or inhibited. Our recent demonstration of neuroendocrine features in proliferating bile ductules in cholestatic liver disease prompted us to perform a similar immunohistochemical and electron microscopical study on regenerating human liver tissue after submassive liver necrosis. In the earliest stages of regeneration, bile ductular cells and small, singular cells in the periportal area expressed chromogranin-A and contained dense-cored, secretory granules. It is tempting to speculate that the scattered singular cells represent the human equivalent of the bipotential progenitor cells in the rat. In later stages of regeneration, these singular cells were no longer evident, suggesting their differentiation into other cell types. In these cases, neuro-endocrine cells corresponded to proliferating bile ductules and to scattered, typical hepatocytes, located near portal tracts and in regenerating nodules. In all cases, proliferating bile ductules displayed the neural cell adhesion molecule (NCAM). These data further support our hypothesis that the substance(s) produced in the dense cored secretory granules may play a role in the growth and/or differentiation of liver cells through an autocrine and or paracrine pathway.