Objective: This prospective cohort study was to evaluate the efficacy and safety of ultrasound-guided High-Intensity Focused Ultrasound (HIFU) in the treatment of uterine adenomyosis. Methods: Ten premenopausal women with symptomatic adenomyosis underwent ultrasound-guided HIFU therapy. Their symptoms were compared using symptom severity scores before and at 3, 6 and 12 months after treatment. The sizes of their uteri and adenomyotic lesions at 6 months after treatment were compared with those of pre-treatment as determined by magnetic resonance imaging. Results: The menstrual pain scores were reduced by 45.5% (-83.3–100%) at 3-month, 57.3% (-83.3–100%) at 6-month and 27.9% (-100–100%) at 12-month after treatment. The modified Uterine Fibroid Symptom and Quality of Life scores were reduced by 50.0% (9.1–69.7%) at 3-month, 40.9% (27.3–66.7%) at 6-month and 39.5% (0–70.0%) at 12-month after treatment. The uterus and adenomyosis volumes were reduced by 24.4% (1.2–42.0%) and 46.3% (2.1-78.4%) at 6-month after treatment, respectively. Two patients (20%) had significant treatment-related complications and three patients (30%) required subsequent surgical interventions. Conclusions: Although ultrasound-guided HIFU appears to provide symptomatic relief to most patients with adenomyosis, its long-term effectiveness and safety require further evaluation in a larger cohort of patients, and may improve with clinical experience.