OBJECTIVES: The aim of this study was to assess whether F-FDG PET combined with x-ray CT (F-FDG PET/CT) findings have a prognostic impact in patients with carcinoma of unknown primary (CUP). PATIENTS AND METHODS: Seventy patients with CUP who were referred for F-FDG PET/CT were included. F-FDG PET/CT results were checked against available histologic diagnosis and follow-up data. For each patient, the SUVmax of the lesion with maximum uptake was measured. RESULTS: In 26% of the patients, a primary tumor was identified. The follow-up period after F-FDG PET/CT scan ranged between 3 and 45 months. Kaplan-Meier analysis revealed 1-year survival rates of 92% in the group without evidence of malignancy on F-FDG PET/CT, 78% in the group with locoregional disease, and 34% in the group with extensive disease on F-FDG PET/CT. Three-year survival rates in these groups were 73%, 71%, and 23%, respectively (P = 0.001). There was no significant survival difference between patients with regionally confined disease without identification of the primary tumor and those in whom the primary tumor was identified on F-FDG PET/CT (P = 0.25). This was also the case for patients with extensive disease (P = 0.26). The SUVmax of the lesion with maximum uptake was not significantly related to survival (P = 0.56). CONCLUSIONS: F-FDG PET/CT is a helpful tool for the identification of the primary tumor in patients with CUP; it is also able to provide an accurate assessment of prognosis based on the extent of the disease without the need for identification of the primary tumor.