Health-related quality of life (HRQL) has been shown to deteriorate as body mass index (BMI) increases. Recent research suggests weight stigma and experiential avoidance may partially account for the relationship between BMI and HRQL. Eighty-seven adults recruited from a weight-loss clinic completed an intake assessment, which consisted of physical measurement taking and completion of self-report measures. Experiential avoidance and weight self-stigma were significant predictors of HRQL and mediated the relationship between BMI and HRQL. Results provide preliminary support for targeting weight stigma and experiential avoidance in order to produce changes in HRQL with or without concurrent weight loss.