Purpose To demonstrate that magnetic resonance (MR) imaging-guided high-intensity focused ultrasound (HIFU) is a safe, effective, and durable treatment option for the management of osteoid osteoma in children and young adults. Materials and Methods This prospective study was institutional review board approved and is registered with clinicaltrials.gov (identification number NCT02302651). Written informed consent was obtained from patients or their parents. Patients who had both clinical and radiologic findings that were diagnostic for nonvertebral osteoid osteoma and no contraindications to MR imaging-guided HIFU were enrolled between June 2010 and June 2013. The feasibility, safety, and clinical effectiveness of MR imaging-guided HIFU were considered primary outcomes; tumor control at imaging was considered a secondary outcome. Analyses were conducted on a per-protocol basis. Results Forty-five of the 50 recruited patients underwent MR imaging-guided HIFU. All patients were discharged without treatment-related complications. The median visual analog scale (VAS) pain score (scale, 0-10) decreased from 8 before treatment to 0 at 1-week and 1- , 6- , 12- , 24- , and 36-month follow-up. Similarly, median VAS scores for the degree to which pain interfered with sleep and physical and daily activities decreased to 0 within the 1st month after treatment and remained stable at subsequent follow-up. Overall, 39 (87%) of the 45 patients achieved and maintained a VAS score of 0 during the 3-year observation period. Quality of life, as assessed by using Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP) scores (scale, 0-60 points), improved, with the median FACT-BP score of 28 (points) before treatment increasing to a median score of 55 at 1-week follow-up and 60 at 6-month and subsequent follow-ups. At (final) 36-month follow-up, MR imaging depicted an absence of residual nidus vascularity in 32 (76%) of the 42 patients who were treated with MR imaging-guided HIFU only. Conclusion The durable clinical efficacy and safety of MR imaging-guided HIFU were demonstrated. These features are evidence of the potential of MR imaging-guided HIFU to be part of a routine strategy for the treatment of osteoid osteoma. RSNA, 2017.