Objectives Obesity is an increasingly prevalent public health concern, with associated medical comorbidities and impairment in health-related quality of life (HRQoL). Obese women are frequently victims of weight-related discrimination. The HRQoL impairments among obese people could be related to this discrimination and to internalized weight bias. Design We examined the potential moderating role of discrimination (from others) and self-directed (internalized) weight-based discrimination in the association between body mass index (BMI) and HRQoL. Methods Eighty-one women (mean age = 41.1 years; mean BMI = 43.40 kg/m2, 97 Caucasian) completed valid and reliable measures of weight bias internalization (weight bias internalization scale), perceived discrimination by others (everyday discrimination scale) and both physical and mental HRQoL (SF-36 Health Survey). Multiple regression analysis was used to test whether internalized weight bias or discrimination moderated the association between BMI and the summary scores for physical and mental HRQoL, controlling for age. Results Significant associations were found between BMI and discrimination (r = .36, p = .002), between internalized weight bias and both mental (r = .61, p <.001) and physical HRQoL (r = .45, p <.001), and between discrimination and physical HRQoL (r = .29, p = .014). A statistically significant interaction was found between BMI and internalized weight bias (b = - .21, SE = .10, p <0.05) in accounting for the variance in physical HRQoL. Conclusions The association between higher BMI and poorer physical HRQoL was found only in individuals reporting high levels of internalized weight bias. Self-discrimination among overweight individuals may be a critical factor in their physical health impairment.