Introduction: The study’s aim was to establish, for children living in urban disadvantage, the nature and extent of the relationship between body mass index (BMI) and health-related quality of life (HRQoL), including the role of individual and family factors in influencing this relationship. Methods: Within the context of a longitudinal design, 255 children aged 7–12 years (50 % male) self-reported their HRQoL (Kidscreen-27) and had their height and weight measured at year one and two. One parent/guardian for each child was also assessed at year one with the OSLO Social Support Scale and Hospital Anxiety and Depression Scale. Regression analysis was also conducted. Results: BMI was weakly inversely associated with ‘total HRQoL’ (r = −.15, p < .05), ‘physical well-being’ and ‘autonomy and parent relations’. Significant differences were found between normal weight and obese children on all but the latter dimension. Neither weight group, however, fell below the average European HRQoL range. BMI predicted physical well-being a year later and vice versa, whilst autonomy and parent relations also predicted BMI a year later. In terms of ‘overweight’ children (38 %), those approaching adolescence had poorer physical and school well-being than younger children, and those whose parents had moderate-to-severe levels of depression fared worse on school well-being than children whose parents were not depressed. Conclusion: The findings suggest that obesity programmes could aim to prevent/reduce obesity and optimise HRQoL in urban disadvantaged preadolescent children whilst also targeting parental mental health difficulties. Future research should examine mediators of the effect of BMI on HRQoL.