•Comparison of DECT biomarkers revealed significant differences between iCCA and HCC.•ID at the arterial phase yielded the best diagnostic performance.•An ID threshold of 2.33 mg/dl was determined to differentiate between both entities. To assess the potential of material decomposition in dual-energy CT (DECT) to differentiate intrahepatic cholangiocarcinoma (iCCA) from hepatocellular carcinoma (HCC). In this retrospective study, we included 94 patients (26 female (27.7 %), median age 64.5 (interquartile range 55.5–74.5) years) with either iCCA or HCC who underwent abdominal contrast-enhanced DECT in arterial phase. To test for differences between iCCA (n = 47) and HCC (n = 47), we evaluated mean attenuation and DECT material density values including iodine density (ID), normalized iodine uptake (NIU), fat fraction, and lesion-to-liver parenchyma ratio. Histopathology served as reference standard for all lesions. We used univariate logistic regression models for the outcome iCCA versus HCC. ROC curve analysis was applied to assess discriminative ability of the model. Model accuracy was evaluated by calculating the Brier score. Youden index was applied to establish thresholds to differentiate between iCCA and HCC. Comparison of quantitative image parameters revealed significant differences between iCCA and HCC for ID (1.6 ± 0.5 mg/ml vs 2.8 ± 0.8 mg/ml, p < 0.001), NIU (14.5 ± 4.8 vs 24.8 ± 10.3, p < 0.001), attenuation (41.9 ± 10.1 HU vs 47.9 ± 8.9 HU, p = 0.003), and fat fraction (12.0 ± 7.8 % vs 9.0 ± 6.4 %, p = 0.045). ROC curve analysis revealed highest ability to differentiate iCCA from HCC for ID (AUC = 0.93, 95 % CI 0.89–0.98). For ID, an optimal threshold of 2.33 mg/dl was determined to discriminate between iCCA and HCC (sensitivity 89.4 %, specificity 76.6 %). DECT-based iodine quantification can serve as a tool for the differentiation of iCCA and HCC in contrast-enhanced CT. ID yielded the highest diagnostic performance and may assist in clinical routine CT diagnostics.