To develop and validate a dual-energy CT (DECT)-based radiomics nomogram from multicenter trials for predicting the histological differentiation of head and neck squamous cell carcinoma (HNSCC).A total of 178 patients (112 in the training and 66 in the validation cohorts) from eight institutions with histologically proven HNSCCs were included in this retrospective study. Radiomics-signature models were constructed from features extracted from virtual monoenergetic images (VMI) and iodine-based material decomposition images (IMDI), reconstructed from venous-phase DECT images. Clinical factors were also assessed to build a clinical model. Multivariate logistic regression analysis was used to develop a nomogram combining the radiomics signature models and clinical model for predicting poorly differentiated HNSCC and moderately well-differentiated HNSCC. The predictive performance of the clinical model, radiomics signature models, and nomogram was compared. The calibration degree of the nomogram was also assessed.The tumor location, VMI-signature, and IMDI-signature were associated with the degree of HNSCC differentiation, and areas under the ROC curves (AUCs) were 0.729, 0.890, and 0.833 in the training cohort and 0.627, 0.859, and 0.843 in the validation cohort, respectively. The nomogram incorporating tumor location and two radiomics-signature models yielded the best performance in training (AUC = 0.987) and validation (AUC = 0.968) cohorts with a good calibration degree.The nomogram that integrated the DECT-based radiomics-signature models and tumor location showed good performance in predicting histological differentiation degree of HNSCC, providing a novel combination for predicting HNSCC differentiation.© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.