Background: High-intensity focused ultrasound (HIFU) represents a new technology in the treatment of uterine fibroids. The curative effect of HIFU is affected by the blood supply of uterine fibroids. Oxytocin is an effective medication for promoting uterine contractions and reducing blood flow to uterine fibroids. This study aimed to evaluate the safety and efficacy of oxytocin-enhanced HIFU in treating uterine fibroids. Methods: A systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted (up to December 14, 2024). Cohort studies reporting the impact of oxytocin on HIFU outcomes were included. A meta-analysis was performed using RevMan 5.3 software, focusing on the non-perfused volume percentage (NPV%). The NPV% is typically used to represent the effective ablated tissue volume, which is then used to calculate the ratio of the non-perfused volume to the volume of the primary fibroids after HIFU treatment. Results: Seven studies met the screening criteria, three of which had a primary outcome measure including NPV%. A meta-analysis showed that oxytocin significantly increased NPV% [mean difference (MD): 13.31, 95% CI: 9.17–17.44; p < 0.00001], with low heterogeneity (I2 = 26.00%). Minimal and transient side effects were reported. Conclusions: Oxytocin enhances the efficacy of HIFU for uterine fibroids by increasing the NPV% and improving procedural outcomes. Nonetheless, further studies are needed to confirm the long-term benefits and safety of oxytocin in conjunction with HIFU. Registration: The study has been registered on https://www.crd.york.ac.uk/prospero/ (registration number: CRD42024627652, registration link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024627652)
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