Background <p>Post-pancreatectomy acute pancreatitis (PPAP) has been increasingly recognized as an independent complication since its formal definition by the International Study Group for Pancreatic Surgery (ISGPS) in 2022. This study aimed to evaluate the diagnostic accuracy of multiparameter assessment of pancreatic parenchyma using dual-layer spectral-detector CT (DLCT) in predicting PPAP after pancreaticoduodenectomy (PD).</p> Methods <p>Consecutive patients who underwent PD and preoperative DLCT between January 2020 and June 2022 were retrospectively analyzed. Iodine concentration (IC) and Hounsfield unit (HU) values of the pancreatic parenchyma were measured in the non-enhanced (N), arterial (A), portal venous (P), and equilibrium (E) phases. CT enhancement patterns were quantified by the A/E ratios of IC and HU values. The extracellular volume (ECV) fraction was calculated based on iodine concentration (ECV. IC) and HU values (ECV. HU) of the equilibrium phase.</p> Results <p>A total of 550 patients were included in the analysis. Of these, 101 (18.3%) patients developed PPAP after PD and had significantly lower IC in the P and E phases compared to those without PPAP (both <i>p</i> &lt; 0.001). Among the composite parameters, the ECV. IC fraction demonstrated the highest accuracy (AUC = 0.784, 95%CI, 0.739–0.829) for predicting PPAP compared to the ECV. HU fraction, A/E HU ratio, (A-N)/(E-N) HU ratio, and A/E IC ratio (AUCs of 0.726, 0.741, 0.743, and 0.751, respectively). On multivariate analysis, an ECV.IC fraction &lt; 30.6% was independently associated with the occurrence of PPAP (OR 7.44, 95% CI: 4.23–13.11, <i>p</i> &lt; 0.001), with sensitivity of 76.2% and specificity of 69.5%.</p> Conclusions <p>Multiparameter assessment of pancreatic parenchyma derived from DLCT showed excellent accuracy for preoperatively predicting PPAP after PD.</p>