Background:Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin. Patients and Methods:We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300-350 mg/m(2)at day 1, 22, and 43 followed by 5FU 600 mg/m(2)/day for 96 h. The other center used cisplatin 100 mg/m(2)at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis-free interval (DMFS), toxicity, and unplanned admissions. Results:In the carbo-5FU cohort (n= 211), 60.2% of the patients completed chemotherapy vs. 76.7% (p<0.001) of the patients in the cisplatin cohort (n= 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09-2.14,p= 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76-1.55,p= 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93-2.01,p= 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74-2.09,p= 0.4) and DMFS (HR 1.08, 95% CI 0.62-1.90,p= 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69). Conclusion:LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS.