The management of patients with unknown primary tumours (UPT) often includes a large number of radiographical studies and invasive procedures, but the occult primary tumour is detected in less than 25%. In this prospective study we explored whether non-invasive whole body PET scans using FDG (18-F-fluorodeoxyglucose) are of clinical value in detection of UPT. Whole-body FDG-PET scans were performed in 20 patients following standard staging procedures according to histology. PET results were verified either histologically or by the clinical course of the disease. 11 patients had neck metastases (5 squamous cell, 5 adenocarcinomas and 1 poorly differentiated carcinoma). The remaining patients had metastases located in bone (3), bone marrow (1), brain (1), pericardium (1), skin (1), pleura (1) and chest wall (1). All metastatic lesions were visible with PET. In 13 patients PET suggested the site for the primary tumour and this was verified in 9 (45%), either histologically or by the clinical course of disease. 8 of these had primary lung cancer and 1 had carcinoma at the basis of the tongue. In most patients PET had no treatment related implications. 3 patients with non-small cell lung cancer (NSCLC) received chemotherapy prompted by the PET result. The rest received either radical radiotherapy to the head and neck region (7), palliative radiotherapy to the metastatic lesion (8), chemotherapy based on signet ring cell carcinoma in bone marrow (1) or no therapy (1). These results indicates that PET is useful in UPT preceding expensive and invasive diagnostic procedures and can result in a faster diagnosis in approximately one third of the patients who then avoid unnecessary extensive procedures. Furthermore, a larger proportion of patients will receive treatment aimed at the correct diagnosis. A prospective cost-effectiveness analysis of PET in this setting is warranted.