Background: There is currently no reliable biomarker for assessing the response to therapy of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated how changes in the tumor/parenchyma interface associate with response. Methods: We reviewed pre- and post-therapy scans of patients who received chemotherapy and/or chemoradiation for both localized and metastatic PDAC. We classified the interface between the PDAC tumor and surrounding pancreas parenchyma as stable (remains or becomes well-defined) or unstable (becomes poorly defined) using a novel visual scoring system and quantified changes in enhancement at this interface (Philips Intellispace Portal, quantitative European Association for the Study of Liver [qEASL]). Results: Three retrospective datasets were used to develop this method with consensus visual scoring performed by 3 radiologists. The first dataset included 99 patients with localized PDAC who received neoadjuvant chemoradiation. Patients who were classified as having a stable interface had significantly higher probability of achieving a complete or near-complete pathologic response (21% vs 0%, p = 0.01) and additionally demonstrated an improved median disease-free survival (DFS, 20.9 vs 7.9 mos., p < 0.01) and overall survival (OS, 47.7 vs 19.1 mos., p < 0.01). These results were validated in a separate dataset of 94 patients receiving protocol-based chemotherapy and chemoradiation (chemoRT cohort) and a cohort of 86 patients with stage IV disease. In both cohorts, a stable interface was associated with a significant improvement in progression free survival (PFS, Hazard Ratio [HR] 0.44, p = 0.01 for chemoRT and HR 0.70, p = 0.16 for stage IV) and OS (HR 0.42, p < 0.01 for chemoRT and HR 0.59, p = 0.05 for stage IV). Multivariate analyses for each cohort showed interface stability to be independently associated with both DFS/PFS and OS. Measurements obtained using qEASL were concordant with the visual scoring results. Conclusions: The interface stability of PDAC is an early readout of response to therapy. Integration of this imaging feature into clinical trials for localized and metastatic PDAC may aid in the future development of adaptive treatment strategies.