Purpose <p>[²¹¹At]YF2 exhibits high cytotoxicity in vitro and prolonged retention in prostate-specific membrane antigen (PSMA) expressing xenografts. Herein we evaluated its therapeutic efficacy in athymic mice with PSMA + PC3 xenografts.</p> Methods <p>The antitumor efficacy of single-dose [²¹¹At]YF2 prepared with HPLC purification and no iodo YF2 carrier (Experiment 1) and without HPLC purification with iodo YF2 carrier (Experiments 2 and 3) was evaluated: Experiment (1) groups of mice (<i>n</i> = 10) received PBS as control, 1.5 MBq, and 2.2 MBq [²¹¹At]YF2; Experiment (2) groups of mice (<i>n</i> = 10) received PBS, 2, 3, 5, or 8 MBq of [²¹¹At]YF2; and Experiment (3) groups of mice (<i>n</i> = 5) received PBS, 9 MBq or 12 MBq [²¹¹At]YF2. After treatment, mice were monitored for tumor growth and body weight, and the maximum tolerated dose (MTD) was determined.</p> Results <p>Co-administration of iodinated YF2 resulted in a 5-fold increase in tumor-to-kidney dose ratio for [²¹¹At]YF2. Significant tumor growth inhibition (TGI) and survival benefit were seen for mice treated with [²¹¹At]YF2, and a single dose of 2.2 MBq led to a 3.6-fold increase in median survival. In second study, a dose-dependent TGI and survival benefit was observed for the treatment groups, with 8 MBq of [²¹¹At]YF2 inducing a 4.5-fold increase in median survival. Radiation toxicity was seen in mice treated with 9 or 12 MBq [²¹¹At]YF2, indicating an MTD of 8 MBq.</p> Conclusion <p>Single dose of [²¹¹At]YF2 showed significant antitumor efficacy and survival benefit at all doses with several long-term survivors, and a single dose of 8 MBq [²¹¹At]YF2 was well tolerated.</p>