Objective: To determine the role of upfront neck dissection (ND) in patient survival and regional control of p16-negative oropharyngeal squamous cell carcinoma (OPSCC) with neck metastases. Design: Retrospective study. Participants: Patients with p16-negative OPSCC with neck metastases, diagnosed between January 1, 2011 and December 31, 2017, and treated with upfront ND followed by chemoradiotherapy (ND + CCRT) or primary chemoradiotherapy (CCRT). Main outcome measures: Recurrence and survival rates were analysed using the Kaplan-Meier method. Results: Data of 67 patients with p16-negative cN+ OPSCC were analysed. Of them, 23 (34.3%) received ND + CCRT and 44 (65.7%) received primary CCRT. At a median follow-up of 37.9 months, the 3-year neck recurrence rate was significantly lower in the ND + CCRT group than in the CCRT group (0% vs. 19%, p=0.031). This trend was more obvious in patients with neck metastases ≥3 cm (0% vs. 32.1%, p=0.045). Survival outcomes were comparable between the groups; notably, the ND + CCRT group received a significantly lower dose of radiotherapy (3-year disease-specific survival: 77.3% and 75.3%, p=0.968, respectively; 3-year disease-free survival: 77.3% and 70.1%, p=0.457, respectively; 3-year overall survival: 62% and 61.8%, p=0.771, respectively between the ND + CCRT and CCRT groups). Conclusion: Upfront ND was significantly beneficial for regional control and resulted in comparable oncological outcomes with a significantly reduced radiation dose. These results findings can help guide the development of a standardised treatment plan for p16-negative OPSCC. Additional prospective studies with larger sample sizes are warranted.