© 2016 Objective Compare human papillomavirus (HPV) status and outcomes in patients undergoing salvage surgical resection for a recurrent oropharyngeal squamous cell carcinoma (OPSCC). Methods Case series with chart review (2005–2013). Results Sixty-nine patients were identified who underwent salvage surgical resection for a recurrent OPSCC after primary radiation therapy. There was no difference in the incidence of HPV negative (52%; n = 36) and HPV positive (48%; n = 33) tumors. The mean time from completion of radiation therapy to salvage surgery was 2.4 years. At the time of salvage operation, there was no correlation with HPV status, as assessed by p16 immunohistochemistry, and lymph node metastases (p = 0.21), T classification (p = 0.22), tracheostomy dependence (p = 0.59), gastrostomy tube dependence (p = 0.82), or duration from radiation therapy (p = 0.63). The majority of patients were either current or former tobacco users (75%) and of the HPV positive patients, 66% were tobacco users. Development of a new recurrence after salvage surgical resection occurred in 33% of patients (n = 26), with a higher incidence in patients with HPV negative disease (52%, n = 17/33; p = 0.05). The overall 2- and 5-year survival rates were 0.47 and 0.23. There was no difference in overall survival rates when stratified by HPV status or tobacco use. Decreased overall 5-year survival rates did correlate with cervical lymph node metastases (p = 0.01), advanced tumor stage (p = 0.04) and dependence on gastrostomy tube postoperatively (p = 0.04). Conclusions This study found cervical lymph node metastases, clinical stage, and dependence on gastrostomy tube for nutrition to have the greatest impact on overall survival for patients with recurrent OPSCC.