Background: Treatment options for refractory angina not amenable to revascularization are limited. Extracorporeal shockwave myocardial revascularization (ESMR) is a novel non-invasive application of low intensity shock waves that stimulates angiogenesis to improve ischemia. We aimed to determine the safety and efficacy of ESMR in patients with refractory angina. Methods: A single-arm multicenter U.S. prospective trial was implemented to assess safety and efficacy of ESMR therapy in patients with Class III/Class IV refractory angina. Each patient received 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy was assessed at baseline and 4 months after treatment by maximal treadmill exercise time and ischemic burden on pharmacological single photon emission computed tomography (SPECT). Safety was assessed by incidence of adverse events, electrocardiography, echocardiography, laboratory markers, and pain questionnaires. Results: Fifteen patients with medically refractory angina were enrolled. Exercise treadmill time from baseline to last follow-up after ESMR increased significantly (38%) by 122.3±156.9 seconds (319.8±157.2 vs. 422.1±183.3 seconds, p=0.016) (Figure 1). There was no difference in the mean summed stress score (SSS) on pharmacological-SPECT 4 months after treatment vs. baseline (17.8±14.9 vs. 21.2±15.3, p=0.233). However, SPECT SSS revealed that untreated areas had greater progression in ischemic burden vs. treated areas (3.69±6.2 vs. 0.31±4.5, p=0.038). There was no significant change in the mean summed echo score from baseline to post treatment (0.4±5.1, p=0.79).There were no changes in electrocardiography, echocardiographic parameters, or laboratory markers. No serious adverse events or complications occurred, and pain with ESMR was minimal (score of 0.5±1.2 to 1.1±1.2 out of 10). Conclusions: We find that ESMR is a safe and efficacious treatment which may be clinically feasible for patients with refractory angina pectoris.