Numerous studies have attempted to identify successful dietary strategies for weight loss, and many have focused on Low-Fat vs. Low-Carbohydrate comparisons. Despite relatively small between-group differences in weight loss found in most previous studies, researchers have consistently observed relatively large between-subject differences in weight loss within any given diet group (e.g., ~25kg weight loss to ~5kg weight gain). The primary objective of this study was to identify predisposing individual factors at baseline that help explain differential weight loss achieved by individuals assigned to the same diet, particularly a pre-determined multi-locus genotype pattern and insulin resistance status. Secondary objectives included discovery strategies for further identifying potential genetic risk scores. Exploratory objectives included investigation of an extensive set of physiological, psychosocial, dietary, and behavioral variables as moderating and/or mediating variables and/or secondary outcomes. The target population was generally healthy, free-living adults with BMI 28-40kg/m (n=600). The intervention consisted of a 12-month protocol of 22 one-hour evening instructional sessions led by registered dietitians, with ~15-20 participants/class. Key objectives of dietary instruction included focusing on maximizing the dietary quality of both Low-Fat and Low-Carbohydrate diets (i.e., Healthy Low-Fat vs. Healthy Low-Carbohydrate), and maximally differentiating the two diets from one another. Rather than seeking to determine if one dietary approach was better than the other for the general population, this study sought to examine whether greater overall weight loss success could be achieved by matching different people to different diets. Here we present the design and methods of the study.