Background Pancreatic fibrosis and fatty infiltration are associated with postoperative pancreatic fistula (POPF), but accurate preoperative assessment remains a challenge. Iodine concentration (IC) and fat fraction derived from dual-energy CT (DECT) may reflect the amount of fibrosis and steatosis, potentially enabling the preoperative prediction of POPF. Purpose To identify multiphasic DECT-derived IC and fat fraction that improve the prediction of POPF risks compared with contrast-enhanced CT attenuation values and to evaluate the underlying histopathologic changes. Materials and Methods This retrospective study included patients who underwent pancreatoduodenectomy and DECT (including pancreatic parenchymal, portal venous, and delayed phase scanning) between January 2020 and December 2020. The relationships of the quantitative DECT-derived IC and fat fraction, along with CT attenuation values from enhanced images with POPF risk, were analyzed with logistic regression analysis. The predictive performance of the IC was compared with that of the CT values. The histopathologic underpinnings of IC were evaluated with multivariable linear regression analysis. Results A total of 107 patients (median age, 65 years; interquartile range, 57-70 years; 56 men) were included. Of these, 23 (21%) had POPF. The pancreatic parenchymal-to-portal venous phase IC ratio (adjusted odds ratio [OR], 13; 95% CI: 2, 162; P < .001) was an independent predictor of POPF occurrence. The accuracy of the pancreatic parenchymal-to-portal venous phase IC ratio in predicting POPF was higher than that of the CT value ratio in the same phases (78% vs 65%, P < .001). The pancreatic parenchymal-to-portal venous phase IC ratio was independently associated with pancreatic fibrosis (β = -1.04; 95% CI: -0.44, -1.64; P = .001). Conclusion A higher pancreatic parenchymal-to-portal venous phase IC ratio was associated with less histologic fibrosis and greater risk of POPF. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Yoon in this issue.