Background <p>The prevalence of hereditary bleeding disorders (HBDs) in heavy menstrual bleeding (HMB) and their impact on health-related quality of life (HRQoL) remain underexplored. We investigated the HRQoL of women with non-structural HMB and its association with HBDs.</p> Method <p>A prospective longitudinal study of 100 women with HMB without structural gynecological pathology. HMB was defined as ≥ 8 days of bleeding or a PBAC score &gt; 100 points. Four HRQoL questionnaires —SF-12^®v2, EQ-5D-3&#xa0;L, MBQ, and SAMANTA— were administered at baseline and 6 months. HBD diagnosis included hypermobility spectrum disorders, von Willebrand disease, platelet disorders, congenital coagulation factor deficiencies, and hyperfibrinolysis.</p> Result <p>88 women required treatment for HMB, anemia, or iron deficiency. Combined hormonal therapy (43%) and levonorgestrel intrauterine devices (14%) were the most frequently used treatments. Thirty-one women (31%) were diagnosed with HBD. After 6 months of treatment, SF-12^®v2 results showed significant improvements in the mental and physical health components, particularly with respect to mobility, moderate activities, and pain perception. EQ-5D-3&#xa0;L evaluations revealed significant improvements in anxiety and depression. MBQ and SAMANTA scores indicated significant reductions in menstrual bleeding and enhanced quality of life. However, at T6, HBD patients showed significantly lower improvements compared with non-HBD patients in physical health (SF-12 PCS, <i>p</i> = 0.035), EQ-5D index scores (<i>p</i> = 0.024), PBAC (<i>p</i> = 0.049), and MBQ (<i>p</i> = 0.028).</p> Conclusion <p>HBD is an important cause of HMB. Medical treatment improves mobility, moderate activities, pain perception, and anxiety/depression after 6 months, although HRQoL improvements are less pronounced in HBD patients.</p>