Obesity is a heterogeneous disease influenced by individual behavioral factors, environment, genes, and neural processes. Behavioral weight loss (BWL), the current gold-standard treatment for overweight and obesity (OW/OB), does not produce sustained weight loss for all individuals. Appetitive traits, such as food responsiveness (FR), are risk factors that could account for differences in how individuals interact with today's food environment and increase susceptibility for overeating and weight gain. Research shows that individuals high in FR have attenuated weight loss in BWL programs. We developed the Regulation of Cues (ROC) program to reduce overeating through improving sensitivity to hunger and satiety cues and decreasing FR. In this study, we combined ROC with BWL recommendations (ROC+BWL), a treatment approach that may address the unique needs of this phenotype. The current study is a 3-arm randomized controlled trial comparing the ROC+BWL program to BWL and an active comparator on body mass index. Two hundred ninety-three adults with high FR and OW/OB were randomized to 1 of 3 treatment arms and will complete 6 months of treatment and assessment visits over 18 months: baseline, during treatment, post-treatment (6 months), 6-month follow-up (12 months) and 12-month follow-up (18 months). This study could provide important evidence regarding the ROC+BWL program among individuals with high FR and OW/OB and may inform future precision medicine approaches for OW/OB. Clinical trials # NCT05004883.