BACKGROUND.: This study evaluates the oncological outcome of patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC) after primary radiation therapy +/- chemotherapy, primary surgical therapy, and surgical therapy followed by radiation therapy +/- chemotherapy. METHODS.: A total of 156 patients (36%) of a cohort of 427 treated for OPSCC between 1990 and 2006 developed recurrent disease. Fifty-one patients (12%) qualified for salvage treatment. Study endpoints were 5-year overall survival (OS) and disease-specific survival (DSS). RESULTS.: The 5-year OS and DSS rates after salvage treatment were 29% and 40%; after initial primary radiation therapy, 25% and 40%; after initial surgery followed by radiation therapy, 40% and 40%; and after initial surgery alone, 20% and 40%. CONCLUSIONS.: Patients with an advanced OPSCC have a considerable risk for recurrence. Despite poor ultimate outcome, salvage treatment should be attempted in patients with resectable disease, good performance status, and absence of distant metastases. (c) 2009 Wiley Periodicals, Inc. Head Neck, 2010.