The aim of this study was to investigate the longitudinal associations between the body size trajectory and the cardio-renal-metabolic (CRM) conditions in adulthood, and evaluate the joint association between body size trajectory and polygenic risk scores (PRS) of CRM conditions.This prospective cohort study included 441,470 UK Biobank participants aged 40 to 70 years, recruited between March 2006 and July 2010. CRM conditions were defined as the occurrence of any of cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes (T2D). Cox regression models and Fine-Gray sub-distribution hazard models were used to estimate associations and competing risks of mortality. Mediation analysis and group-based trajectory modeling were performed to assess mediation effects and body size change trajectories. Additionally, interaction analyses were conducted to examine the combined effects of between the body size trajectories and PRS on CRM conditions.The incidence density of CRM conditions was 128.9 per 1,000 person-years. Adulthood overweight/obesity mediated the association between childhood plumper body size and CRM conditions (mediation proportion = 55.82%, P<0.0001). Five trajectories of body size from birth to adulthood were identified, and the other four trajectories differing from the "normal-average-normal" trajectory were associated with increased risks of CRM conditions, with hazard ratio (HR) and 95% confidence interval (CI) ranging from 1.20 (1.15, 1.26) to 1.32 (1.28, 1.37). Intermediate and high genetic risk groups demonstrated elevated increased risks of CVD, CKD, and T2D, and the additive interactions were found between body size trajectories and PRS on CKD and T2D.Maintaining a normal body size across the life cycle, even with intermediate or high genetic risk, may help mitigate the impact of genetic risk. Early monitoring and interventions aimed at sustaining a normal body size throughout life could provide life-course benefits in preventing CRM conditions, particularly for individuals with elevated genetic risk.Copyright © 2025. Published by Wolters Kluwer Health, Inc.