PROJECT SUMMARY/ABSTRACT This is a new application proposing to conduct the SUBstituting with Preferred OPtions (SUB-POP) trial, a parallel-arm RCT to test the effects of substituting SSBs with non-caloric options on body weight and markers of T2D and cardiometabolic health. Eligible adult participants will be randomized to 1 of 4 beverage groups (N=135 per group) at the baseline in-person visit and all will receive at-home monthly deliveries of beverages via Amazon for 6 months. In-person clinic visits will be conducted at baseline, 6, and 12 months. After the 6 months of assigned beverage substitution and delivery, all participants will be instructed to substitute SSBs with water only for a final 6 month observational period. In-person clinic visits will collect technician-measured anthropometrics, blood pressure, biospecimen samples (blood, urine, stool [subset n=50 per group]), and questionnaires (physical activity, beverage frequency), and taste preference test. The SUB-POP app-based assessments and online diet recall will ascertain repeated measures of beverage adherence, diet, physical activity, and appetite in the interim, every 3 months. A subset (n=60 per group) will receive at home Wi-Fi digital scales to measure body weight approximately daily for novel energy balance and caloric compensation modeling. Our proposal will leverage the many strengths and state-of-the-art clinical trial infrastructure of the Division of Preventive Medicine at BWH. The highly collaborative investigator team is comprised of experts in nutritional and obesity epidemiology, clinical trial design, implementation and analysis, energy balance and weight loss, and interpretation for public health dietary guidelines. SUB-POP is a novel RCT that will enroll adult regular SSB consumers with overweight or obesity to evaluate the effectiveness of substituting SSBs with non-caloric options in a real-world, un-blinded setting. Our trial will leverage modern recruitment methods, achieve ≥30% non-White participants, implement innovative intervention delivery, adherence, and data collection tools, and partition the two most common artificial sweetener types to explore potential heterogeneity. It is unknown whether ASBs, which are largely free of calories and sugar, provide a healthful interim strategy to transition to water among habitual SSB consumers. Thus, by addressing this large gap in our understanding of how to address a highly prevalent and concerning dietary exposure, we will inform dietary guidelines and clinical recommendations for the prevention of obesity, T2D, and cardiometabolic disease risks.