BACKGROUND AND OBJECTIVE: The diagnostic approach to newly detected space-occupying lesions in the liver can be difficult and a histogenetic classification of the primary tumor is impossible in some cases. Such cases of metastatic disease without a detectable primary tumor are classified as cancer of unknown primary site (CUP). The incidence of this diagnosis depends on the clinical and histochemical methods used. It was the main aim of this study to analyze the true incidence of adenocarcinoma metastases of the liver with an unknown primary cancer after application of a standardized protocol of clinical and immunhistochemical diagnostic tests and a long-term follow-up. PATIENTS AND METHODS: Between January 2000 and January 2003 127 consecutive patients underwent diagnostic ultrasound-guided biopsy of a space-occupying lesion in the liver. Based on the histopathology and immunochemistry a well defined and individually adapted diagnostic algorithm was employed (endoscopy, imaging). RESULTS: 44 females and 83 males, median age 66.8 years, were enrolled into the study. Primary tumors of the liver were found in 21 cases and non-hepatocellular tumors (metastases) were documented in 106 patients, 82 of the latter (77%) had metastases of an adenocarcinoma. The further diagnostic approach was based on histochemistry, immunhistochemistry and imaging techniques, making possible a full diagnosis of primary tumor in a further 59 (72%) cases. Thus the incidence of an adenocarcinoma of the liver of unknown primary site was 23 of 127 cases (18%). CONCLUSIONS: Although there is a wide variety of modern diagnostic methods today, the histogenetic classification of hepatic metastases is not always possible. However, in the last few years diagnostic advances have occurred based on modern immunhistochemical methods. This immunhistochemical definition has made it possible to avoid an oppressive "overdiagnosis" and offer patients early and appropriate therapeutic options.