T he prevalence of obesity has increased dramatically over the last decades in many industrialized countries, such that they are experiencing what has often been referred to as an obesity epidemic.1 Average body mass index (BMI) worldwide has increased by ≈0.5 kg/m 2 per decade since the 1980s, and an estimated 500 million adults were considered obese (BMI ≥30 kg/m 2 ) in 2008. 2 The trends in France are consistent with this general pattern, with an average relative increase in BMI of almost 6% per year since 1997 and a prevalence of obesity of 15% in 2009. 3 This rapid rise is a major public health concern because of the strong evidence for associations between excess body weight and increased mortality and morbidity. [4][5][6] The relationship between BMI and health-related quality of life (HRQoL) has been investigated in a variety of settings, including health centers for weight loss, general medicine practices, and population-based studies. [7][8][9][10][11][12][13][14][15][16][17][18] Most reports consistently show the following: (1) there is a J-or U-shaped relationship linking physical HRQoL and BMI, with higher risk for poorer HRQoL in the underweight and overweight/ with obesity subjects; (2) findings for psychosocial impairment are inconclusive and detect little or no effect; [7][8][9][10][11]13,19,20 (3) physical, and to a lesser extent psychosocial, impairment is more severe in women than men. 7,8,11,12,[21][22][23] There are few data available to explain the different consequences of obesity between the sexes because most analyses exploring the relationship between BMI and HRQoL account for sex as a confounder to adjust for and do not report stratified results. Among the various explanations that have been proposed, a higher discomfort caused by overweight has been observed in women, 24 and women have been found to develop body image dissatisfaction at higher rates compared with men. 25 Differences in prevalence and impact of obesityrelated medical comorbidities have also been suggested, suchBackground-Negative effects of obesity on health-related quality of life (HRQoL) have been reported, especially in women, but the relative contribution of cardiometabolic and other obesity-related comorbidities to such effects remains unclear. Our objective was to model the association by sex between body mass index and HRQoL and to precisely quantify the indirect effects mediated by obesity-related comorbidities. Methods and Results-Data were drawn from the latest French Decennial Health Survey, a nationwide cross-sectional study conducted in 2003 (21 239 adults aged 25-64 years analyzed). HRQoL was measured by the 36-item short-form health survey questionnaire. A mediation analysis based on the counterfactual framework was performed to quantify the proportion of obesity effects on HRQoL mediated by related comorbidities, including cardiometabolic risk factors (diabetes mellitus, hypertension, dyslipidemia) and diseases (ischemic heart disease, cerebrovascular, and peripheral vascular disease), musculoskelet...