IMPORTANCE: Patients with stage T2 multilesion angiosarcomas of the scalp and face that are larger than 10 cm demonstrate a 2-year survival rate of 0%. To our knowledge, major therapeutic advances against this disease have not been reported for decades. Preclinical data indicate that blocking β-adrenergic signaling with propranolol hydrochloride disrupts angiosarcoma cell survival and xenograft angiosarcoma progression. OBSERVATIONS: A patient presented with a β-adrenergic-positive multifocal stage T2 cutaneous angiosarcoma (≥20 cm) involving 80% of the scalp, left forehead, and left cheek, with no evidence of metastasis. The patient was immediately administered propranolol hydrochloride, 40mg twice a day, as his workup progressed and treatment options were elucidated. Evaluation of the proliferative index of the tumor before and after only 1 week of propranolol monotherapy revealed a reduction in the proliferative index of the tumor by approximately 34%. A combination of propranolol hydrochloride, 40mg 3 times a day, paclitaxel poliglumex, 2mg/m2 infused weekly, and radiotherapy during the subsequent 8 months resulted in extensive tumor regression with no detectable metastases. CONCLUSIONS AND RELEVANCE: Our data suggest that β-blockade alone substantially reduced angiosarcoma proliferation and, in combination with standard therapy, is effective for reducing the size of the tumor and preventingmetastases. If successful, β-blockade could be the first major advancement in the treatment of angiosarcoma in decades.