Abstract: Objective To analyze theoretically the optimal dose-fractionation of intensity-modulated radiotherapy in head and neck squamous cell carcinoma (HNSCC). Methods The common dosefractionation of 33 division, keeping the irradiation dose of 70 Gy, biological effect dose (BED) of 84Gy10 and prolong overall treatment time was applied to simulate different dose and time treatment, respectively. The linear-quadric function was used to calculate the tumor, early response (mucosal), late response BED and the tumor log10 cell kill with different fraction number and/or dose to fi nd out the optimal fractionation. Results With 33 fractions, the fraction dose and total irradiation dose varied from 2.12-2.30 Gy and 70.0-75.9 Gy respectively. The doses of tumor, mucosal and late effect BED were 69.6Gy-78.2Gy10, 55.5-64.1Gy10, and 119.4-129.5Gy3 respectively. The tumor log10 cell kill was 10.6-11.9. While keeping the physical irradiation dose of 70 Gy or BED of 84Gy10, the fraction dose ranged from 2.20-2.80 Gy with 25-35 fractions and the total treatment day (TTD) was 32-46. The doses of tumor, early and late response BED were 67.5-82.3Gy10, 53.1-69.8Gy10, and 113.5-119.8Gy3 respectively and the tumor log10 cell kill was 10.3-12.5. Taking the tumor, early and late response BED and tumor cell log10 kill into comprehensive consideration, the regimen with 30 daily IMRT fractions can balance the tumor control and radiation-related toxicity well. For every single prolonged day, the tumor BED decreased 1.4% (0.8Gy10) and the tumor log10 cell kill did 0.1. Conclusion The optimal dose-fraction in IMRT of HNSCC is theatrically 30 daily fractions in six weeks. And the tumor BED will decrease with the prolonged overall treatment days.