Objective: To assess the prospective relationship between obesity and health-related quality of life, including a novel assessment of the impact of health-related quality of life on weight gain. Design and setting: Longitudinal, national, population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study, with surveys conducted in 1999/2000 and 2004/2005. Participants: A total of 5985 men and women aged X25 years at study entry. Main outcome measure(s): At both time points, height, weight and waist circumference were measured and self-report data on health-related quality of life from the SF-36 questionnaire were obtained. Cross-sectional and bi-directional, prospective associations between obesity categories and health-related quality of life were assessed. Results: Higher body mass index (BMI) at baseline was associated with deterioration in health-related quality of life over 5 years for seven of the eight health-related quality of life domains in women (all Pp0.01, with the exception of mental health, P40.05), and six out of eight in men (all Po0.05, with the exception of role-emotional, P ¼ 0.055, and mental health, P40.05).Each of the quality-of-life domains related to mental health as well as the mental component summary were inversely associated with BMI change (all Po0.0001 for women and Pp0.01 for men), with the exception of vitality, which was significant in women only (P ¼ 0.008). For the physical domains, change in BMI was inversely associated with baseline general health in women only (P ¼ 0.023). Conclusions: Obesity was associated with a deterioration in health-related quality of life (including both physical and mental health domains) in this cohort of Australian adults followed over 5 years. Health-related quality of life was also a predictor of weight gain over 5 years, indicating a bi-directional association between obesity and health-related quality of life. The identification of those with poor health-related quality of life may be important in assessing the risk of future weight gain, and a focus on health-related quality of life may be beneficial in weight management strategies.