Purpose: To investigate the prognostic value of differential enhancement on baseline dual-energy CT images in patients with treatment-naive pancreatic ductal adenocarcinoma (PDAC), with a focus on tumor-host interface characterization. Materials and Methods: This was a retrospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study of 158 consecutive adult patients (mean age, 68 years; age range, 40.9-88.9 years; 50% women) with histopathologically proven, treatment-naive PDAC, who had undergone multiphasic pancreatic dual-energy CT from December 2011 to March 2017. Regions of interest in tumor core, tumor border, pancreas border with tumor, nontumoral pancreas, and aorta were recorded on pancreatic parenchymal phase (PPP) dual-energy CT 70-keV, 52-keV, and iodine material density (MD) images, plus portal venous phase (PVP) conventional CT images. Enhancement gradient (delta) across the tumor-pancreas interface was calculated. Delta was evaluated combining the dual-energy CT values with the PVP values and as individual predictors. Receiver operating characteristic analysis with logistic regression was used to determine the optimal cut point for each dual-energy CT delta to predict disease outcome based on highest Youden index. Survival curves were generated using Kaplan-Meier method, and comparison between two independent groups (high and low delta) was evaluated with log-rank test. Clinical outcomes included overall survival and distant metastasis-free survival. Three independent blinded radiologists visually scored tumor conspicuity (subjective delta score) on a 1-5 scale, and agreement was evaluated with κ statistic. Results: Ninety-three patients had advanced stage (50 locally advanced and 43 metastatic) and 65 had lower stage (48 resectable and 17 borderline resectable) tumors. Patients with high delta tumors (≥ 40 HU) on either 70-keV PPP images or conventional PVP images had significantly shorter overall survival compared with those with low delta tumors (< 40 HU) in both early stage PDAC (13.5 months vs 23.3 months; hazard ratio [HR], 1.87; 95% confidence interval [CI]: 1.01, 3.5; P = .04) and advanced stage PDAC (10.8 months vs 18.0 months; HR, 2.1; 95% CI: 1.28, 3.6; P = .003). Qualitative visual scoring of tumor conspicuity also showed shorter overall survival in patients with more conspicuous tumors. Highest interreader agreement for subjective delta score was 0.73 and 0.60 using iodine MD and 52-keV images, respectively. Conclusion: Increased quantitative and qualitative border conspicuity (high delta) is associated with shorter survival in patients with PDAC. Agreement on the subjective qualitative characterization of PDAC borders is best achieved using iodine MD and lower-energy simulated monoenergetic images at pancreatic protocol dual-energy CT.Keywords: Abdomen/GI, CT, CT-Dual Energy, CT-Quantitative, PancreasSupplemental material is available for this article.© RSNA, 2020.