Background Recent consensus statements and clinical trials have assessed the value of MRI-guided focused ultrasound surgery for pain palliation of bone metastases; however, a comparison with external beam radiation therapy (EBRT) has not been performed. Purpose To compare safety and effectiveness data of MRI-guided focused ultrasound and EBRT in the treatment of bone metastases. Materials and Methods Participants with painful bone metastases, excluding skull and vertebral bodies, were enrolled in a prospective open-label nonrandomized phase II study between January 2017 and May 2019 and underwent either MRI-guided focused ultrasound or EBRT. The primary end point was the overall response rate at 1-month following treatment, assessed via the numeric rating scale (NRS) for pain (0-10 scale, with zero meaning "no pain" and 10 meaning "the worst pain imaginable"). Secondary end points were improvements at 12-month follow-up in NRS and quality of life (QoL) measures, including the Brief Pain Inventory (BPI), QoL-Questionnaire Cancer-15 Palliative Care (QLQ-C15-PAL), and QoL-Questionnaire Bone Metastases-22 (QLQ-BM22) and analysis of adverse events. Statistical analyses, including linear regression, χ2 test, and Student t test followed the per-protocol principle. Results Among 198 participants, 100 underwent MRI-guided focused ultrasound (mean age, 63 years ± 13 [SD]; 51 women), and 98 underwent EBRT (mean age, 65 years ± 14; 52 women). The overall response rates at 1-month follow-up were 91% (91 of 100) and 67% (66 of 98), respectively, in the focused ultrasound and EBRT arms (P < .001), and complete response rates were 43% (43 of 100) and 16% (16 of 98) (P < .001). The mean baseline NRS score was 7.0 ± 2.1 for focused ultrasound and 6.6 ± 2.4 for EBRT (P = .16); at 1-month follow-up, they were reduced to 3.2 ± 0.3 and 5.1 ± 0.3 (P < .001), respectively. QLQ-C15-PAL for physical function (P = .002), appetite (P < .001), nausea and vomiting (P < .001), dyspnea (P < .001), and QoL (P < .001) scores were lower in the focused ultrasound group. The overall adverse event rates were 15% (15 of 100) after focused ultrasound and 24% (24 of 98) after EBRT. Conclusion MRI-guided focused ultrasound surgery and external beam radiation therapy showed similar improvements in pain palliation and quality of life, with low adverse event rates. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kelekis in this issue.