© 2022Objective: The aim of this systematic review is to gather and synthesize evidence regarding the use of oral gonadotrophin-releasing hormone (GnRH) antagonist for the treatment of bleeding associated with uterine myomas. Data Sources: Web of Science, and MEDLINE databases were searched electronically on March 5, 2021, using combinations of the relevant Medical Subject Headings terms and keywords. The search was restricted to the English language and to human studies. Methods of Study Selection: Only randomized controlled trials involving patients with heavy menstrual bleeding associated with uterine myomas treated with different doses of oral nonpeptide GnRH antagonists with or without add-back therapy were included. Studies comparing oral nonpeptide GnRH antagonists with treatments other than placebo were also excluded. Tabulation, Integration, and Results: A total of 5 randomized trials including 2463 women were included in the analyses. Included studies were found to be at low risk of bias. When treatments were compared against placebo, the top 3 treatments for bleeding suppression were elagolix 600 mg, 400 mg, and 200 mg without add-back. Elagolix 600 mg without add-back therapy had a significantly higher risk of amenorrhea than lower doses of elagolix with and without add-back and relugolix as well. Uterine volume changes were more pronounced in therapies without add-back. All treatments were associated with significantly improved quality of life scores, both for myoma symptom–related and overall health-related scores. With the exception of relugolix with high-dose add-back, all treatments significantly increased low-density lipoprotein (LDL) levels. Again, all treatment modalities except for elagolix 200 mg without add-back significantly increased LDL-to-HDL ratio. The increase was highest for treatment without add-back therapy. Conclusion: Oral GnRH antagonists seem to be effective for myoma-associated bleeding and for improving quality of life. The safety profile is acceptable for short-term use, but lipid metabolism is affected.