We have studied apoptosis in a subset of thirty hepatocellular carcinomas (HCCs) exhibiting neuroendocrine differentiation (ND). Apoptosis was assessed by use of in situ DNA end labelling, and was quantified employing a TdT labelling index. It turned out that apoptosis occurred in HCCs with ND, albeit at different rates. Apoptosis was visualized as a clearly detectable reaction product mostly localized in tumor cell nuclei and in apoptotic bodies. Almost no staining was observed in nuclei of multinuclear tumor giant cells. In HCCs with ND, apoptosis was not related to type or grade, but tumors mainly consisting of hepatocyte-like cells and/or clear cells showed a significantly higher apoptotic rate. This was also the cell type most frequently disclosing neuroendocrine features. The apoptotic rate was significantly higher in HCCs with ND than in a control group of HCCs not showing ND. The findings suggest that neuroendocrine differentiation in liver cell tumors is associated with an altered pattern of programmed cell death, and that this phenomenon may therefore have an influence on clinical behavior.