Abstract Background Addition of nimotuzumab to weekly cisplatin and radiation improves outcomes in head and neck cancer. HPV-negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. Hence we wanted to determine whether the addition of nimotuzumab to cisplatin-radiation can improve outcomes in these subsets of poor-risk tumors. Methods This was a subgroup analysis of a phase 3 randomized study. In this study locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin (30 mg/m2 IV )- radiation (66-70 Gy) {CRT arm} or nimotuzumab (200 mg weekly) -weekly cisplatin (30 mg/m2)-radiation (66-70 Gy) {NCRT arm}. The data for HPV-negative oropharyngeal cancer was extracted from the database of this study for the current analysis. HPV testing was done with p16 IHC staining and reported according to the CAP criteria. The outcomes assessed were progression-free survival (PFS), disease-free survival (DFS), locoregional control (LRC), and overall survival (OS). Interaction test was performed between the study arms and HPV status prior to doing any HPV-specific analysis for each of the studied outcomes. Kaplan Meier estimates for 2-year OS with 95% CI is provided. The hazard ratio was calculated using Cox regression analysis. Results We had 187-HPV negative oropharyngeal cancers, 91-CRT arm and 96 in NCRT arm. The interaction test was significant for PFS (p = 0.000), locoregional control (p = 0.007) and overall survival (p = 0.002) but not for DFS (p = 0.072). The 2-year PFS was 31.5% (95%CI 21.5-42) in CRT arm versus 57.2% (95%CI 45.8-67.1) in NCRT arm (HR -0.54;95%CI 0.36-0.79, p = 0.002). While the 2-year LRC was 41.4 % (95%CI 29.8-52.6) in CRT arm versus in 60.4% (95%CI 48.7-70.2) in NCRT arm (HR -0.61;95%CI 0.4-0.94, p = 0.024). The addition of nimotuzumab also led to an improvement in OS from 39.0% (95%CI 28.4-49.6) to 57.6% (95%CI 46.3-67.4) (HR-0.63, 95%CI 0.43-0.92, p = 0.018). Conclusions The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV-negative oropharyngeal cancers. Clinical trial identification CTRI/2014/09/004980. Legal entity responsible for the study The authors. Funding Biocon Ltd, TRAC. Disclosure K. Prabhash: Research grant / Funding (institution): Dr. Reddy’s Laboratories Inc; Research grant / Funding (institution): Fresenius Kabi India Pvt Ltd; Research grant / Funding (institution): Alkem Laboratories; Research grant / Funding (institution): Natco Pharma Ltd; Research grant / Funding (institution): BDR Pharmaceutics Intl Pvt Ltd; Research grant / Funding (institution): Roche Holding AG. V. Noronha: Research grant / Funding (institution): Dr. Reddy’s Laboratories Inc; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Sanofi Aventis. All other authors have declared no conflicts of interest.