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Objective: To quantitatively characterize change in health-related quality of life (HRQoL) in the context of behavioral (n = 16), surgical (n = 5), and pharmacological (n = 1) interventions for pediatric overweight and obesity. A secondary goal was to examine the relationship between change in HRQoL and change in body mass index (ΔBMI) by treatment type. The amount of weight loss necessary to observe a minimally clinically important difference (MCID) in HRQoL was determined. Method: Data were gathered from studies reporting on weight change and ΔHRQoL over the course of obesity interventions (N = 22) in youths (N = 1,332) with average ages between 7.4 and 16.5 years (M = 12.2). An overall effect size was calculated for ΔHRQoL. Moderation analyses were conducted using analysis of variance and weighted regression. MCID analyses were conducted by converting HRQoL data to standard error of measurement units. Results: The overall effect size for ΔHRQoL in the context of pediatric obesity interventions was medium (g = 0.51). A significant linear relationship was detected between ΔBMI and ΔHRQoL (R2 = 0.87). This relationship was moderated by treatment type, with medical (i.e., surgical) interventions demonstrating a stronger relationship. Results indicated that it takes a change of 0.998 BMI units to detect true change in HRQoL. Conclusion: This study provides the first known quantitative examination of changes in HRQoL associated with weight loss in pediatric interventions. Medical interventions appear to offer a more substantial increase in HRQoL per unit of BMI change. These results offer a concrete weight loss goal for noticing positive effects in daily life activities.