Introduction: Preoperative prediction of histological response to neoadjuvant therapy is a remarkable findings for making decision of surgical resection in borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). No prospective study reported investigating surrogate marker to predict their histological response to neoadjuvant therapy. Method: Twenty-eight patients with BRPC and LAPC who underwent diffusion-weighted magnetic resonance imaging (DW-MRI) prior to expected neoadjuvant chemotherapy and surgery were reviewed prospectively. Analyses for correlation between percent tumor cell destruction and the following was performed to investigate the parameter and cut off value: tumor size, whole tumor or vascular abutment site apparent diffusion coefficient (ADC) value of DW-MRI, maximum standardized uptake value of 18F-fluorodeoxyglucose positron emission tomography, carbohydrate antigen 19-9, and their change ratios or differences. The strong parameters were assessed for prediction ability of the therapeutic histological response and R0 curability. Result: Pre/post-treatment ADC value was correlated with tumor cell destruction rate among all parameters (R=0.630/0.714, P<0.001/<0.0001). The pre/post-treatment ADC cut-off value for discriminating between grade I and grade IIa and more after treatment was determined as 1.17/1.36x10-3 mm2/s and the sensitivity, 83/100%; specificity, 73/77%; accuracy, 75/82% for response, and the sensitivity, 63/75%; specificity, 75/80%; accuracy, 71/79% for R0 curability. The pre/post-treatment ADC cut-off value for discriminating between grade -3 mm2/s and the sensitivity, 92/100%; specificity, 63/81%; accuracy, 75/89% for response, and the sensitivity, 63/88%; specificity, 70/70%; accuracy, 68/75% for R0 curability. Conclusion: Post-treatment ADC value were confirmed to be a predictor of R0 curability in patients with BRPC and LAPC, and there was a significant correlation between the pre/post-treatment ADC value and histological tumor cell destruction rate.