PURPOSE: Health-related quality of life (HRQOL) refers to an individual's perception of their physical and mental health status over time. Although emerging evidence has documented a negative association between weight stigma (i.e., negative weight-related attitudes and beliefs towards individuals with overweight or obesity) and mental HRQOL, its influence on physical HRQOL still needs to be fully clarified. This study aims to investigate the impact of internalized weight stigma on mental and physical HRQOL by employing a structural equation modeling (SEM) approach. METHODS: The Short Form Health Survey 36 (SF-36) and the Weight Bias Internalization Scale (WBIS) were administered to a sample of 4450 women aged 18-71 (M = 33.91 years, SD = 9.56) who self-identified in a condition of overweight or obesity (M = 28.54 kg/m; SD = 5.86). Confirmatory factor analysis (CFA) was conducted to assess the dimensionality of the scales before testing the proposed structural model. RESULTS: After establishing the adequacy of the measurement model, SEM results revealed that internalized weight stigma was significantly and negatively associated with both mental (β = - 0.617; p < 0.001) and physical (β = - 0.355, p < 0.001) HRQOL. CONCLUSION: These findings offer additional support to prior research by confirming the association between weight stigma and mental HRQOL. Moreover, this study contributes to the existing literature by strengthening and extending these associations to the physical HRQOL domain. Although this study is cross-sectional in nature, it benefits from a large sample of women and the use of SEM, which offers advantages over traditional multivariate techniques, e.g., by explicitly accounting for measurement error. LEVEL OF EVIDENCE: Level V, descriptive cross-sectional study.