Objective Primary angiosarcomas originating from the heart, aorta, or great vessels are extremely rare and hence poorly understood. We reviewed our experience to identify a preferred diagnostic and treatment strategy and evaluate the role of adjunctive therapy. Methods We reviewed the clinical data of all patients diagnosed with primary angiosarcoma of the heart, aorta, and great vessels from 1985 to 2011, including presentation, diagnosis, management, and outcomes. Results Thirteen patients (five males and eight females; mean age, 54 ± 4 years) had primary angiosarcoma arising from the aorta (n = 7), heart (n = 3), pericardium (n = 2), and pulmonary artery (n = 1). Patients with aortic tumors most commonly presented with lower extremity claudication (n = 2), renovascular hypertension (n = 3), abdominal pain (n = 5), and weight loss (n = 4). Patients with cardiac and pericardial tumors presented with dyspnea (n = 5) due to pleural effusion or cardiac tamponade. All 13 patients underwent computed tomographic scan, which demonstrated irregular, lobulated mass/thrombus with peripheral enhancement, and eight patients underwent diagnostic echocardiography. Metastatic disease was present in 10 patients. The most common site was the lungs (n = 6). All except one patient exhibited high-grade morphology histopathologically. Nine patients were treated surgically: resection with aortic reconstruction (n = 5), thromboendarterectomy (n = 2), pericardiectomy/atrial septal resection with patch reconstruction (n = 2), and just biopsy (n = 1). Adjunctive treatment included chemotherapy (n = 6) and radiation (n = 4). Median survival was 8 months (range, 1-75 months). Patients treated with all three treatment modalities had longer survival than did patients treated with a single modality (P = .013). Patients treated with chemotherapy had a more favorable survival than did those without chemotherapy (P = .048). Conclusions Primary angiosarcoma of the heart and great vessels is rare but is a harbinger of poor prognosis. Pathologic examination is necessary to confirm the diagnosis. Combined therapy with surgical resection and chemoradiotherapy offers patients the best survival.