Maximizing the benefits of investments in obesity research requires effective interventions to be adopted and disseminated broadly across populations (scaled-up).However, interventions often need considerable adaptation to enable implementation at scale, a process that can reduce the effects of interventions. A systematic review was undertaken for trials that sought to deliver an obesity intervention to populations on a larger scale than a preceding randomized controlled trial (RCT) that established its efficacy. Ten scaled-up obesity interventions (six prevention and four treatment) were included. All trials made adaptations to interventions as part of the scale-up process, with mode of delivery adaptations being most common. A metaanalysis of body mass index (BMI)/BMI z score (zBMI) from three prevention RCTs found no significant benefit of scaled-up interventions relative to control (standardized mean difference [SMD] = 0.03; 95% CI, −0.09 to 0.15, P = 0.639 − I 2 = 0.0%). All four treatment interventions reported significant improvement on all measures of weight status. Pooled BMI/zBMI data from prevention trials found significantly lower effects among scaled-up intervention trials than those reported in prescale-up efficacy trials (SMD = −0.11; 95% CI, −0.20 to −0.02, P = 0.018 − I 2 = 0.0%). Across measures of weight status, physical activity/sedentary behaviour, and nutrition, the effects reported in scaled-up interventions were typically 75% or less of the effects reported in pre-scale-up efficacy trials. The findings underscore the challenge of scaling-up obesity interventions.