The consequences of obesity are ominous, yet we are not adequately preventing or treating obesity in youth with Down Syndrome (DS). In DS, obesity has been linked to adverse health outcomes. In addition, obesity further limits one’s independence, ability to optimally function, self-manage health and creates additional challenges for caregivers. Total daily energy expenditure (TDEE) is the energy expended in a 24-hour period through physical activity and physiologic processes. An individual’s TDEE is essential for determining daily caloric intake needed to maintain or change body weight. Furthermore, TDEE is the foundation of anticipatory guidance provided by health care professionals to optimize growth and weight management. Successful prevention and treatment of obesity in youth with DS is severely compromised by the lack of accurate data on TDEE and information on weight-related behaviors for this high-risk population. This prospective, cross-sectional study will include a sample of 230 youth with DS, (stratified by age and sex). Doubly Labeled Water (DLW) analysis will provide the criterion body fat%, fat-free mass and TDEE. Study participants will be recruited nationally, utilizing DS-Connect® and DS family focused organizations. To increase accessibility, support enrollment, and decrease burden on participants, all data collection will be conducted virtually. Using DLW, this study will, 1) examine and describe average TDEE based on age and sex, 2) develop a prediction equation based on actual TDEE to predict energy requirements with a best-fit model based on fat- free mass, sex, age, and height and/or weight, and 3) use 24-hour dietary recalls, a nutrition and physical activity screener, accelerometers, and sleep questionnaire to describe the patterns and quality of dietary intake and sleep and duration and frequency of physical activity in youth with DS. This will provide further understanding of weight-related behaviors as obesity determinants, currently not well understood for this population. The lack of accurate information on energy expenditure and weight-related behaviors in youth with DS significantly impedes successful prevention and treatment of obesity for this vulnerable population. Findings from the proposed study will advance the science of weight management in individuals with disabilities, address national research priorities, and shift clinical practice paradigms.