Summary Purpose: The biological behaviour of prostate cancer is highly variable and prediction by the commonly employed prognostic parameters is not sufficient. The concept of neuroendocrin e (NE) differentiation in prostate adenocarcinoma has recently received increasing attention due to possible implications for prognosis and therapy. Materials and methods: Core needle biopsies from 142 newly diagnosed patients were immunohistochemically examined for the coexistence of NE differentiation using an antibody against chromogranin A (CgA). Circulating CgA was available in 106 of these patients. Results: NE differentiati on was found in 64 (45.1%) tumors. Among them 29 (20.4%) had CgA positive cells scattered or focally distributed in less than 5% per mm3 of tumor tissues, 26 (18.3%) between 5% and 10% and 9 (6.4%) more than 10%, respectively. There was a significant correlation between the extent of NE features and either Gleason score {P < 0.01) or stage of disease. Circulating CgA but not PSA correlated with immunohistochemical CgA {P < 0.03) particularly in metastatic cases. Conclusions: These data support the concept that NE differentiation in human prostate cancer has a negative prognostic significance. Circulating CgA levels reflect immunohistochemical findings.