SummaryThe relationship between BMI and health‐related quality of life (HRQoL) critically affects regulatory approval of interventions for weight loss, but evidence of the association is inconsistent. A higher standard of evidence than that available was sought with an IPD meta‐analysis of 10,884 people enrolled in five randomized controlled trials of intentional weight loss interventions. Cross‐sectional and longitudinal associations of BMI and HRQoL were estimated in mixed effects models specifying a latent variable for HRQoL. Spline regressions captured nonlinear associations across the range of BMI. In cross‐sectional spline regressions, BMI was not associated with HRQoL for people with a BMI < 30 kg/m² but was for those with a higher BMI. In longitudinal spline regressions, decreases in BMI were positively associated with HRQoL for people with a BMI ≥ 25 kg/m². The impact of change in BMI was larger for people with higher BMIs than for those with BMIs under 30 kg/m². Lower BMI and decreases in BMI were related to higher HRQoL for people living with obesity but not in the population without excess weight. HRQoL gains from weight loss are greater for more severe obesity. Commissioners should use these estimates for future decision making.