Although intra-cardiac masses are rare, diagnosis and refined characterization of these masses are important because of the different therapeutic strategies used to treat these lesions. The purpose of this study was to evaluate the diagnostic value of dual-energy cardiac computed tomography (CCT) for differentiating cardiac myxomas from thrombi. Our institutional review board approved this study, and patients provided informed consent. We prospectively enrolled 37 patients who had an intra-cardiac mass on echocardiography or computed tomography (CT). All patients underwent dual-energy CCT. For quantitative analysis, the CT attenuation density and iodine concentration of the intra-cardiac mass were measured on CT images. The Mann-Whitney test was used to evaluate differences in the mean CT attenuation density and the mean iodine concentrations between the cardiac myxoma and thrombus groups. Pathological results or follow-up with echocardiography was used to make the final diagnosis. There were a total of 17 cardiac myxomas and 20 thrombi. On CT, the mean CT numbers were not significantly different between cardiac myxomas and cardiac thrombi (91.7 ± 11.6 HU vs. 85.2 ± 10.9 HU, respectively, P = 0.241), whereas, the mean iodine concentration (mg/ml) was significantly different between cardiac myxomas and cardiac thrombi (3.53 ± 0.72 vs. 1.37 ± 0.31, respectively, P < 0.001). Dual-energy CCT using a quantitative analytic methodology can be used to differentiate between cardiac myxomas and thrombi.