Objectives Multiple types of mediastinal masses, especially masses in the anterior mediastinum, may be encountered in routine echocardiographic examinations for symptomatic or asymptomatic patients. The aim of this study was to evaluate the diagnostic value of transthoracic echocardiography combined with contrast-enhanced ultrasonography in determining the location, composition, and vascularization of mediastinal masses. Methods A retrospective analysis was conducted on 48 consecutive patients who first had a diagnosis of mediastinal masses by echocardiography. The location of the mass, tissue components, and relationships with the heart and great vessels were analyzed on the basis of multiple transthoracic echocardiographic views. Further contrast-enhanced ultrasonography was performed to determine the vascularization of masses in 25 patients. The clinical, computed tomographic, and histopathologic findings were all recorded and analyzed. Results The localization, ultrasonographic characteristics of the mass, degree of vascularization, and relationships with the heart and great vessels assessed on echocardiography allowed a correct diagnosis in most of the cases. Conclusions Transthoracic echocardiography is a useful method for diagnosing mediastinal. Further contrast-enhanced ultrasonography could provide more details on the degree of vascularization, which could facilitate accurate diagnosis and differentiation diagnosis.