ABSTRACT Approximately 35% of children in the U.S. have overweight or obesity (OW/OB). To date, the most successful weight loss program for children is Family-Based Treatment (FBT), which is delivered to both children and parents and includes nutrition and physical activity education, behavior therapy techniques, and parenting skills. Data suggest that 2/3 of children who participate in FBT do not respond. This lack of success suggests that there are unaddressed mechanisms that could be impacting treatment response. The Behavioral Susceptibility Theory purports that food cue responsiveness (FR) is the primary driver of eating onset, while satiety responsiveness (SR) is the primary driver of eating offset. High FR is a risk factor that influences weight loss maintenance among children who participate in FBT. We developed a new model for the treatment of children with OW/OB, called Regulation of Cues (ROC), which is based on the Behavioral Susceptibility Theory. The ROC program targets these mechanisms for overeating, by focusing on reducing FR and increasing SR. We pilot tested the ROC model with children who overeat with OW/OB, and showed that the ROC program is feasible, acceptable and is a promising treatment for children. The objective of this proposed study is to further evaluate the ROC program among children with OW/OB who are high on FR and their parents. We propose a multisite 4-arm randomized controlled trial at UC San Diego and University of Minnesota that will compare ROC, FBT, ROC+ nutrition education and caloric restriction (ROC+) and a health education comparator (HE) over 18 months. We will recruit and randomize 280 children with OW/OB who are high on FR and their parents and will conduct assessments at baseline, throughout treatment, post-treatment, and at 6- and 12-month follow-up. The primary aim of this study is to evaluate changes in child weight (BMIz/%BMIp95) as well as overeating episodes among children enrolled in ROC, FBT, ROC+ and HE. Secondary aim 1 will compare ROC, FBT, ROC+ and HE on child SR, FR, inhibition, and energy intake over the course of the treatment and follow-up. Secondary aim 2 will compare ROC, FBT, ROC+ and HE on parent outcomes, including weight loss (BMI), overeating episodes, satiety responsiveness, food cue responsiveness inhibition, and energy intake over the course of treatment and follow-up. Finally, exploratory aim 1 will evaluate effects of mediators (food cue responsiveness, satiety responsiveness, inhibition) and moderators (food cue responsiveness, satiety responsiveness, demographics, baseline BMIz/%BMIp95/BMI) of treatment effects on weight loss over time among children and parents. This study could provide a more durable weight loss program for children with OW/OB and high FR and has the potential to change the paradigm of weight-loss treatment for children. This study will also contribute to the study of basic appetitive mechanisms and food intake and inform clinical decision making for ...