Objectives:We aim to characterize the serial quantitative apparent diffusion coefficient (ADC) changes of the target disease volume using diffusion-weighted imaging (DWI) acquired weekly during radiation therapy (RT) on a 1.5T MR-Linac and correlate these changes with tumor response and oncologic outcomes for head and neck squamous cell carcinoma (HNSCC) patients as part of a programmatic R-IDEAL biomarker characterization effort.Methods:Thirty patients with pathologically confirmed HNSCC who received curative-intent RT at the University of Texas MD Anderson Cancer Center, were included in this prospective study. Baseline and weekly Magnetic resonance imaging (MRI) (weeks 1-6) were obtained, and various ADC parameters (mean, 5th, 10th, 20th, 30th, 40th, 50th, 60th, 70th, 80th, 90thand 95thpercentile) were extracted from the target regions of interest (ROIs). Baseline and weekly ADC parameters were correlated with response during RT, loco-regional control, and the development of recurrence using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the weekly ADC versus baseline values. Weekly volumetric changes (Δvolume) for each ROI were correlated with ΔADC using Spearman’s Rho test. Recursive partitioning analysis (RPA) was performed to identify the optimal ΔADC threshold associated with different oncologic outcomes.Results:There was an overall significant rise in all ADC parameters during different time points of RT compared to baseline values for both gross primary disease volume (GTV-P) and gross nodal disease volumes (GTV-N). The increased ADC values for GTV-P were statistically significant only for primary tumors achieving complete remission (CR) during RT. RPA identified GTV-P AADC 5thpercentile >13% at the 3rdweek of RT as the most significant parameter associated with CR for primary tumor during RT (p <0.001). Baseline ADC parameters for GTV-P and GTV-N didn’t significantly correlate with response to RT or other oncologic outcomes. There was a significant decrease in residual volume of both GTV-P & GTV-N throughout the course of RT. Additionally, a significant negative correlation between mean ΔADC and Δvolume for GTV-P at the 3rdand 4thweek of RT was detected (r = − 0.39, p = 0.044 & r = − 0.45, p = 0019, respectively).Conclusion:Assessment of ADC kinetics at regular intervals throughout RT seems to be correlated with RT response. Further studies with larger cohorts and multi-institutional data are needed for validation of ΔADC as a model for prediction of response to RT.