Associations among gender, overweight and obesity, medical comorbidity, and health-related quality of life (HRQoL) were examined in a general population sample of 4,181 women and men aged 18-65 years. Anthropometric measurements and medical comorbidity were assessed as part of a computer-assisted physician interview. HRQoL was assessed with the Physical and Mental Component Summary scales of the Medical Outcomes Study Short Form (SF-36 PCS, MCS). General linear models were used to examine the associations among gender, weight status, medical comorbidity, and HRQoL. Controlling for age, social status, the occurrence of specific medical conditions, and the total number of medical conditions, mild obesity was associated with impairment in physical health functioning, as measured by the PCS, among women, whereas impairment in men's physical health was apparent only for moderate obesity. There was no association between weight status and psycho-social functioning, as measured by the MCS, in women, whereas overweight was associated with better perceived psycho-social functioning in men. The findings are consistent with the hypothesis that women suffer a disproportionately large share of the disease burden of overweight and obesity that is not due solely to differences in medical comorbidity. The possibility that aspects of emotional well-being may mediate the association between obesity and physical health functioning warrants further attention in this regard. The findings also indicate the need to stratify data by gender and to include more sensitive measures of psycho-social functioning in future studies.