Objective. The objective of this study was to compare the efficacy of surveillance high-resolution computed tomography (HRCT) and physical examination/endoscopy (PE/E) with the efficacy of fluorodeoxyglucose (FDG)-positron emission tomography (PET)/HRCT for the detection of relapse in head and neck squamous cell carcinoma (HNSCC) after primary treatment. Methods. This is a retrospective analysis of contemporaneously performed FDG-PET/HRCT, neck HRCT, and PE/E in 99 curatively treated patients with HNSCC during post-therapy surveillance to compare performance test characteristics in the detection of early recurrence or second primary cancer. Results. Relapse occurred in 19 of 99 patients (20%) during a median follow-up of 21 months (range: 9 -52 months). Median time to first PET/HRCT was 3.5 months. The median time to radiological recurrence was 6 months (range: 2.3-32 months). FDG-PET/ HRCT detected more disease recurrences or second primary cancers and did so earlier than HRCT or PE/E. The sensitivity, specificity,andpositiveandnegativepredictivevaluesfordetectinglocoregionalanddistantrecurrenceorsecondprimarycancer were 100%, 87.3%, 56.5%, and 100%, respectively, for PET/HRCT versus 61.5%, 94.9%, 66.7%, and 93.8%, respectively, for HRCT versus 23.1%, 98.7%, 75%, and 88.6%, respectively, for PE/E. In 19 patients with true positive PET/HRCT findings, a significant change in the management of disease occurred, prompting either salvage or systemic therapy. Of the 14 curatively treated patients, 11 were alive with without disease at a median follow-up of 31.5 months. Conclusion. FDG-PET/HRCT has a high sensitivity in the early detection of relapse or second primary cancer in patients with HNSCC, with significant management implications. Given improvements in therapy and changes in HNSCC biology, appropriate modifications in current post-therapy surveillance may be required to determine effective salvage or definitive therapies. The Oncologist 2013;18:1108 -1117 Implications for Practice: The role of PET/CT in the post-therapy surveillance of head and neck cancer is not defined by prospective studies, but cumulative retrospective data support the use of FDG-PET/CT in this setting. By corroborating prior results, we believe that we have an important message for physicians and health insurance carriers, that after completion of primary definitive treatment, surveillance PET/CT detects relapse earlier than both diagnostic CT and NCCN-recommended conventional methods. Although retrospectively, we report a significant change in disease management after PET/CT results suggested a survival benefit compared with reported historical data. We found that most patients had recurrence in the first 2 years after completion of therapy, and PET/CT detected most recurrences within the first 6-month period. Our findings corroborate those of other authors, and therefore, there is merit to recommending a post-therapy scan 3-4 months after completion of therapy, followed by another scan within the first year and scanning every 6 months ...