Background: We conducted an investigator-initiated, phase 3 randomized study to evaluate the efficacy and toxicity of addition of Nimotuzumab during concurrent chemoradiation in locally advanced squamous head and neck cancer (LASHNC). Methods: Adult subjects (age ≥ 18 years), with stage III-IV, LASHNC, Karnofsky performance status of ≥ 70 and adequate organ function were randomized 1:1 into either radical radiotherapy (66-70 Gy) with weekly cisplatin (30 mg/m2) (CRT arm) or the same schedule of chemoradiation along with weekly Nimotuzumab (200 mg) (NCRT arm). The primary endpoint was progression free survival (PFS) and the other key secondary endpoints were disease free survival (DFS), duration of locoregional control (LRC) and overall survival (OS). Intent to treat analysis was performed. The planned sample size was 536 for superiority margin of 12%, assuming PFS of 60% with 80% power and alpha of 0.05. Results: 536 patients were equally allocated between both arms. The median follow up was 33.0 months (95%CI 30.7-35.2 months). The PFS was significantly longer in the patients treated in the NCRT arm (2 year PFS 58.9% versus 49.5%, HR = 0.74; 95% CI 0.56-0.95; P = 0.022). The median duration of PFS was 60.3 months (95% CI 29.4-NA) in the NCRT arm (P = 0.023) and 21 months (95% CI 15.1-NA) in the CRT arm. Addition of Nimotuzumab improved the LRC (HR = 0.75; 95% CI 0.57-0.97, P = 0.030), DFS (HR = 0.75; 95% CI 0.57-0.97, P = 0.030) and had a trend towards improvement in OS (HR = 0.85, 95% CI 0.65-1.10, p = 0.222). Grade 3-5 adverse events (CTCAE version 4.03) were similar between the 2 arms except for the higher incidence mucositis in the NCRT arm (66.7% versus 55.8%, p = 0.010). Conclusion: In conclusion, Nimotuzumab in combination with cisplatin and radiotherapy was superior to cisplatin and radiotherapy in improving the PFS, LRC and DFS. This combination provides a new therapeutic option in the armamentarium against LASHNC. Clinical trial information: CTRI/2014/09/004980.