BACKGROUND: Patients older than 40 years presenting with osteolytic bone lesions are likely to have a diagnosis of carcinoma, even if they had no prior cancer diagnosis. For patients with no prior cancer diagnosis, there is a well-accepted algorithm to determine a potential primary site. That algorithm, however, leaves approximately 15% of people without a detectable primary tumor site, making treatment decisions extremely difficult. Positron emission tomography (PET) fused with CT, more commonly known as PET/CT, has emerged as an important staging modality for many other malignancies but has been used in a very limited fashion in musculoskeletal oncology. QUESTIONS/PURPOSES: We asked (1) What is the ability of PET/CT to detect the source of the primary tumor in patients with a skeletal metastasis of unknown primary? (2) How does PET/CT perform in detecting metastases in other sites in patients with a skeletal metastasis of unknown primary? METHODS: A retrospective analysis between 2006 and 2016 of the pathology database of a single tertiary center identified 35 patients with a biopsy-proven skeletal metastasis (histologically confirmed carcinoma or adenocarcinoma) and a PET/CT scan that was performed after the standard diagnostic evaluation of the primary cancer site. Patients were identified through use of our pathology database to identify all biopsy-proven bone carcinomas. This was then cross referenced with our imaging database to identify all patients who were at any time evaluated with PET/CT. During this time, we identified 1075 patients with biopsy-proven metastatic bone disease through our pathology database. Any indication for a PET/CT was included, and was most often done for staging of the identified malignancy or evaluation for the unknown source. Data regarding the ability of PET/CT to find or confirm the primary cancer and all metastatic sites were evaluated. The standard diagnostic evaluation (history and physical, laboratory evaluation, CT of the chest/abdomen/pelvis and whole body bone scan) identified the primary cancer in 22 of the 35 patients. Among the 35 patients, there were a total of 176 metastatic sites of disease identified, with 115 identified with the standard diagnostic evaluation (before PET/CT). RESULTS: Among patients with a skeletal metastasis of unknown primary, PET/CT was unable to identify the primary cancer in 12 of 13 patients. PET/CT confirmed the site of the known primary cancer in all 22 patients. There were 176 total metastatic sites. Of the 115 metastases known before PET/CT, PET/CT failed to identify three of 115 (3% false-negative rate). CONCLUSIONS: PET/CT may not provide any additional benefit over the standard evaluation for identification of the primary cancer in patients with a skeletal metastasis of unknown primary, although it may have efficacy as a screening tool equivalent or superior to the standard diagnostic algorithm for evaluation of the overall metastatic burden in these patients. LEVEL OF EVIDENCE: Level III, diagnostic study.