Background: Neoadjuvant chemotherapy (NACT) with DCF (Docetaxel, Cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer (LAOC) and has a survival advantage over the CF (Cisplatin and 5FU) regimen. DC regimen (Docetaxel, Cisplatin) had shown promising results in small series, with a lower rate of adverse events but has never been compared with DCF. Methods: This was a phase 3 open-label superiority randomized study. Adult patients with very LAOC (technically unresectable), ECOG PS 0-2 and adequate organ function were eligible. They were randomly assigned in a 1:1 fashion to either DCF or DC regimen. After the administration of 2 cycles, these patients were evaluated in the multidisciplinary clinic. Based on the response, further treatment either surgery followed by adjuvant or radical chemoradiation or palliative therapy was planned. The primary endpoint was overall survival (OS). The key secondary endpoint was adverse events. Results: 495 patients were randomized in this study, 250 patients in arm A and 245 in arm B. At a median follow-up of 39.5 months. The 2-year OS was 29.1% in the DCF and 23.5% in the DC arm respectively (HR=0.81; 95%CI 0.66-0.99, P-value= 0.043). Grade 3 or above adverse events were higher in the DCF arm - oral mucositis (10.6% versus 1.2%), diarrhea (13.6% versus 9.6%), febrile neutropenia (23.2% versus 2.6%), hyponatremia (40.8% versus 20.8%), and hypokalemia (17.9% versus 1.6%). Conclusions: NACT with DCF has a survival benefit over DC in oral cancers but it comes at the cost of an increment in acute adverse events. Clinical trial information: CTRI/2016/04/006804.