Introduction Angiosarcoma is a rare and aggressive malignancy with a high metastatic potential and recurrence rate. Despite optimal treatment with surgery, with or without radiation, the prognosis remains poor and, therefore, new treatment strategies are warranted. Recently, propranolol has effectively been repurposed for the treatment of infantile haemangioma. Propranolol is a β3-sparing antagonist of the β-adrenergic receptor. In infantile haemangioma, the β1, β2 and β3 receptors are highly expressed. Angiosarcoma has several similarities with haemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. As a result, propranolol has been administered small scale in individual angiosarcoma cases with promising results. The precise effect of propranolol, however, is not yet established. Methods and analysis The goal of this neoadjuvant window of opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. The neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in standard anticancer treatment. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during 3-6 weeks, before the initiation of standard treatment. The primary endpoint is clinical response according to Response Evaluation Criteria in Solid Tumours, as measured on consecutive coloured photographs or CT/MRI. The histological response will be determined as secondary endpoint, comparing the difference in proliferation index before and after propranolol by measuring the change in immunohistochemistry staining of Ki-67. The study will be considered positive when at least three patients have a response to propranolol. Ethics and dissemination Ethical approval was obtained from the Medical Ethical Committee of the Netherlands Cancer Institute. Independent of the outcome, results of this study will be shared and submitted for publication in an international peer-reviewed journal. Trial registration number NL8118; registry through the Netherlands Trial Register.