ObjectiveTo determine the cost‐effectiveness of surveillance imaging with PET/CT scan among patients with human papillomavirus‐positive oropharyngeal squamous cell carcinoma.Study DesignCost‐effectiveness analysis.SettingOncologic care centers in the United States with head and neck oncologic surgeons and physicians.MethodsWe compared the cost‐effectiveness of 2 posttreatment surveillance strategies: clinical surveillance with the addition of PET/CT scan versus clinical surveillance alone in human papillomavirus‐positive oropharyngeal squamous cell carcinoma patients. We constructed a Markov decision model which was analyzed from a third‐party payer's perspective using 1‐year Markov cycles and a 30‐year time horizon. Values for transition probabilities, costs, health care utilities, and their studied ranges were derived from the literature.ResultsThe incremental cost‐effectiveness ratio for PET/CT with clinical surveillance versus clinical surveillance alone was $89,850 per quality‐adjusted life year gained. Flexible fiberoptic scope exams during clinical surveillance would have to be over 51% sensitive or PET/CT scan cost would have to exceed $1678 for clinical surveillance alone to be more cost‐effective. The willingness‐to‐pay threshold at which imaging surveillance was equally cost‐effective to clinical surveillance was approximately $80,000/QALY.ConclusionDespite lower recurrence rates of human papillomavirus‐positive oropharyngeal cancer, a single PET/CT scan within 6 months after primary treatment remains a cost‐effective tool for routine surveillance when its cost does not exceed $1678. The cost‐effectiveness of this strategy is also dependent on the clinical surveillance sensitivity (flexible fiberoptic pharyngoscopy), and willingness‐to‐pay thresholds which vary by country.