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Background: Radical radiotherapy with concurrent high-dose cisplatin (100mg/m2/3 weeks) (HDC) chemotherapy is standard of care in the non-surgical management of locally advanced head and neck squamous cell carcinoma (HNSCC). However, many patients are not eligible to receive this regimen due to poor performance status or medical co-morbidities. Low-dose cisplatin (40mg/m2/week) (LDC) is an alternative, but as robust data is still lacking, it is not known if LDC is as effective as HDC. We aimed to add insight to this matter, by reviewing our experience in treating unresectable locally advanced HNSCC. We presented intermediate results at ESMO 2015 Congress in Vienna: the 1-year overall survival (OS) was improved with HDC compared to LDC. We present the final results with the 2-year disease-free survival (DFS) and OS of these patients. Methods: Patients with locally advanced HNSCC who received radical radiotherapy associated with either HDC or LDC between december 2008 and december 2013 were retrospectively reviewed. Patients who did not complete their radiotherapy course and those who received chemoradiotherapy in adjuvant setting were excluded. Results: 72 patients were analyzed (42 in HDC regimen and 30 in LDC regimen). Most patients had carcinoma of the hypo- and oropharynx (75%). Median age was similar in the two regimens (57 years), as well as median performance status (Karnofsky index of 90%). The median number of administered cycle in the HDC and the LDC was 2 (range 1-3) and 5 (range 3-7), respectively. The estimated median DFS was 21,0 ± 8,5 months in HDC compared to 15,0 ± 11,6 months in LDC regimen (P=0.159) ; the estimated 2-year DFS was 50,0% and 43,3%, respectively. The estimated median OS was 84,0 ± 34,1 months in HDC compared to 24,0 ± 6,1 months in LDC regimen (P=0.042) ; the estimated 2-year OS was 64,3% and 50,0%, respectively. Grade 3 hematologic toxicities were observed at the same frequency (16%) in the two regimens, as well as grade 3 mucitis (34% in HDC versus 30% in LDC). Conclusion: This limited retrospective monocentric analysis showed an improvement of median overall survival with HDC compared to LDC in patients with locally advanced HNSCC treated with definitive chemoradiotherapy. Toxicities appeared similar between the two groups.