We have analyzed neuroendocrine differentiation (ND) in hepatocellular carcinomas (HCCs) of fifty patients. It turned out that ND is frequent in HCCs, and that it is not restricted to fibrolamellar hepatocellular carcinoma (FL-HCC). Multiexpression is seen in a quarter of the cases, and marker coexpression may occur within the same tumor cell. ND predominates in trabecular and mixed HCCs, but does not appear to be related to grade. Most positive cases showed a hepatocyte-like cell morphology, frequently associated with bile formation. It thus appears that the HCC cell type most likely to show ND is a hepatocyte-like one, i.e. differentiated cell, frequently polarized and producing bile, rather than a small and poorly-differentiated cell. Possible pathogenic mechanisms leading to ND in HCCs are briefly discussed.