ABSTRACT Two out of every three adults has overweight or obesity, which is associated with significant medical and psychological consequences. To date, the most successful weight loss treatment is behavioral weight loss (BWL), which includes nutrition and physical activity education, as well as behavior therapy techniques. Although some adults lose weight in these programs, one third to one half do not respond with even bleaker rates of weight loss maintenance over time. These low success rates suggest that there are underlying mechanisms, such as appetitive traits, that may interfere with response to BWL and underscore the critical need to develop targeted models for the treatment of obesity. Our data suggest that high food responsiveness (FR) is a risk factor for failure in BWL. We have developed a new model for the treatment of obesity based on the Behavioral Susceptibility Theory, called Regulation of Cues (ROC), that focuses on decreasing FR and improving satiety responsiveness (SR). In this study, we propose to recruit adults with overweight and obesity who also exhibit high levels of FR to test the efficacy of an enhanced ROC treatment program (ROC+) for this specific behavioral phenotype. We propose a 3 arm randomized controlled trial that will compare ROC+, BWL and an active comparator (AC). We will recruit and randomize 300 adults with overweight and obesity and will assess them at baseline, during treatment, post-treatment, and at 6- and 12-month follow-up. Primary and secondary aims are as follows. Primary Aim 1: Compare ROC+ to AC on body mass index (BMI) over the course of treatment and follow-up. Primary Aim 2: Compare ROC+ to BWL on body mass index (BMI) over the course of treatment and follow-up. Secondary Aim 1: Compare BWL to AC on body mass index (BMI) over the course of treatment and follow-up. Secondary Aim 2: Compare ROC+, BWL and AC on sensitivity to satiety, sensitivity to food cues, inhibition, restriction, caloric intake, and overeating over the course of the treatment and follow-up. Exploratory aim 1: Evaluate effects of mediators (FR, SR, restriction, overeating) and moderators (demographics, baseline BMI) of treatment effects on weight loss over time. This program of research is an important next step in the development of treatments for specific phenotypes of adults with overweight/obesity, and could change the paradigm of obesity treatment for these individuals. This study will contribute to the study of appetitive phenotypes of obesity, will provide a targeted treatment for individuals with high FR, and could inform clinical decision making for adults with obesity.