We conducted a retrospective review of the records of 23 patients who had been diagnosed with regionally metastatic head and neck squamous cell carcinoma from an unknown primary tumor. Our goal was to assess the utility of panendoscopy in locating the primary tumor in those patients whose positron-emission tomography/computed tomography (PET/CT) findings were negative. Overall, we found that PET/CT had correctly identified the unknown primary in 12 of the 23 patients (52%); panendoscopy confirmed this finding in all 12. Of the remaining 11 patients, however, panendoscopy located the primary tumor in only 1 (9%). In this era of cost containment and ongoing advances in imaging and transnasal esophagoscopy, it is important to revisit the workup of an unknown primary in patients with a negative PET/CT scan. There are various advantages and disadvantages to performing panendoscopy with biopsy in patients with an unknown primary and a negative PET/CT scan, but our results and the findings of others indicate that it will detect the primary in only about 10% of these cases. We recommend careful selection of patients who are to undergo panendoscopy for the routine workup of an unknown primary.