It is critical to distinguish between cardiac tumors and thrombi because they require different treatment strategies. Although accurate differentiation of these cardiac masses can be challenging, computed tomography (CT) and magnetic resonance imaging (MRI) are promising tools to improve their diagnosis. This study aimed to assess the diagnostic value of a volume-based quantification strategy using dual-energy CT to differentiate between cardiac tumors and thrombi. We prospectively enrolled 41 patients who had a cardiac mass. All patients underwent electrocardiography gated dual-energy CT. Among them, 28 patients underwent late gadolinium enhancement cardiac MRI. For quantitative analysis, the following parameters of the entire cardiac masses were measured: CT attenuation values in Hounsfield units (HU), iodine concentration (mg/ml), and signal intensity (SI) ratio. A mixed effects model was used to evaluate the significance of differences in mean CT attenuation, mean iodine concentration, and SI ratios between the cardiac tumor and thrombus groups. Diagnostic performance of each parameter was evaluated by constructing a receiver operating characteristics curve. A total of 24 cardiac tumors and 19 cardiac thrombi were analyzed. The mean iodine concentration was significantly higher in tumors than in thrombi (tumors: 2.98 ± 0.23; thrombi: 1.79 ± 0.26, p = 0.002). The diagnostic performance of iodine concentration was better than that of post-contrast HU (area under the curve [AUC]: 0.77 vs. 0.51; p < 0.001), and worse than that of SI ratio (AUC: 0.89; p = 0.04) for differentiation of cardiac tumors and thrombi. Dual-energy CT using volume-based iodine measurements can differentiate between cardiac tumors and thrombi.