Purpose: To investigate the predictive value of serial diffusion-weighted MRI (DWI) on tumor response of the concurrent chemoradiotherapy (CCRT) for esophageal squamous cell carcinoma (ESCC) and to determine the optimal time point of DWI measurements. Methods and materials: From June 2010 to October 2011, 38 ESCC patients were consecutively enrolled into this prospective cohort study. During their treatment, the longitudinal DWIs were acquired at beginning and every week during the course of CCRT. ADC maps were generated from there DWIs. The tumor responses were evaluated according to the RECIST. Results: (1) At completion of CCRT, 20 (52.6%) and 18 (47.4%) patients were evaluated as CR and PR, respectively. Over the time points of measures, the series of ADC values (10(-3) mm(2)/s) in whole GTV were consistently characterized with higher (all p < 0.05) for these CR patients as their means (std) were 2.24 (0.49), 2.23 (0.51), 2.44 (0.57), 2.54 (0.52), 2.70 (0.46), 2.80 (0.55), 2.92 (0.62), compared with these PR patients as 1.83 (0.31), 1.79 (0.21), 1.87 (0.30), 1.97 (0.37), 2.15 (0.44), 2.26 (0.46), 2.32 (0.51), respectively. However, the ADC change rates (Delta ADC) of two groups were found to be similar. These results were also supported by the multivariate ANOVA analyses. The same analysis results of DWI based GTV volumes were also found. (2) The comparisons of logistic regression analysis indicated that only the ADC values at Week 3 (15 fractions) were an independent prognostic factor of tumor response (OR = 0.303, p = 0.003). ROC curve analysis showed that Area Under Curve for ADC values of the end of 2nd and 3rd weeks were biggest (0.822) and the prediction efficacy was comparatively optimized. The corresponding cut-off values were 2.11 and 2.14 (10(-3) mm(2)/s), respectively. (3) Additional analyses on those eight patients with tumor local recurrence within 1 year demonstrated the level-off after the continuously increased ADC values till Week 4. Conclusions: DWI can be used as a biomarker to predict TE of esophageal cancers in early time during CCRT. The treatment-induced change in ADC of whole GTV during the first 2-3 weeks can be highly predictive to TE. The unchanged ADC value in late period may indicate the high tendency of tumor recurrence after 1 year. (C) 2016 Elsevier Ireland Ltd. All rights reserved.