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Relugolix-combination therapy (CT) (oestradiol 1 mg and norethindrone acetate 0.5 mg) is a new gonadotropin-releasing hormone antagonist licensed to treat heavy menstrual bleeding (HMB) associated with uterine fibroids; but little real-world data exists to guide practice. To evaluate the efficacy and safety of relugolix-CT in women with fibroid-associated HMB in two large Italian hospitals. A retrospective multicentre study was conducted on 102 women with symptomatic fibroids and HMB, defined as a Pictorial Blood Assessment Chart (PBAC) score >100, who were treated with relugolix-CT for up to 24 months. Women were divided into three groups: group 1 (n=81) receiving only relugolix-CT treatment; group 2 (n=11) receiving at least two months of relugolix-CT prior to hysteroscopic, laparoscopic or open myomectomy; group 3 (n=10) receiving at least two months of pre- and post-myomectomy relugolix-CT. The primary outcome was resolution of HMB, defined as a PBAC score <100. Secondary outcomes included the side effects of treatment. The population mean age was 43.8 years (±6.06), and the mean baseline PBAC score was 329.9 (± 217 standard deviation). In women treated with relugolix-CT alone, 71 (94.7%) responded after two months. By nine months, only 36 (44.4%) women continued with relugolix-CT. Resolution of HMB was sustained in most women who continued treatment at each follow-up time point. By two months prior to myomectomy, HMB resolved in all women receiving relugolix-CT pre-surgery and nine (90%) women continuing relugolix-CT after myomectomy. No major side effects were reported. This real-world study supports previous controlled trial data showing relugolix-CT to be a safe, efficacious medical treatment for HMB with fibroids. Real-life clinical data support the use of relugolix-CT to treat symptomatic fibroids in isolation or combined with myomectomy.