IMPORTANCE This study addresses the most common initial symptoms of oropharyngeal squamous cell carcinoma (OPSCC) and investigates differences between human papillomavirus (HPV)–positive vs HPV-negative tumors. OBJECTIVES To analyze the most common initial symptoms in patients with OPSCC and to determine if any differences in initial symptoms occur between HPV-positive and HPV-negative tumors. DESIGN, SETTING, AND PATIENTS Retrospective single-institution review of medical records of previously untreated patients with OPSCC diagnosed from January 1, 2008, toMay 20, 2013, who were evaluated by 1 physician (the senior author, T.A.D.) at the Medical University of South Carolina. MAIN OUTCOMES AND MEASURES We determined the most common initial symptoms of OPSCC and analyzed differences between HPV-positive and HPV-negative tumors. RESULTS Neck mass (in 39 patients [44%]) and sore throat (in 29 patients [33%]) comprised the most common initial symptoms in OPSCC. Patients who were HPV-positive were more likely to initially notice a neck mass than HPV-negative patients (51% vs 18%; P = .02), whereas HPV-negative patients were more likely to notice sore throat (53%vs 28%; P = .09), dysphagia (41% vs 10%; P = .05), or odynophagia (24%vs 6%; P = .04). CONCLUSIONS AND RELEVANCE This study provides preliminary evidence supporting neck mass and sore throat as the initial symptoms of patients with OPSCC. Patients who were HPV-positive more commonly complained of a neck mass as the initial symptom, whereas HPV-negative patients more commonly had symptoms related to the primary tumor site, including sore throat, dysphagia, and/or odynophagia.