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Funding Acknowledgements Type of funding sources: None. Background Body weight is associated with frailty and is an independent strong predictor of adverse outcomes among patients with cardiovascular diseases. Purpose To evaluate how body mass index (BMI) and frailty modify the association of significant tricuspid regurgitation (TR) with poor survival. Methods Consecutive echocardiographic reports linked to clinical data from a tertiary medical center (2007–2021) were reviewed. Patients with BMI between 14 and 45 Kg/m2 were included, with the first echocardiography as the index case. Significant TR was defined as moderate-to-severe or severe. BMI categories included underweight, normal weight, overweight and obesity with cutoffs of 18.5, 25 and 30, respectively. Frailty was stratified into 3 groups. The primary outcome was all-cause mortality and was available for all patients. Multivariable Cox regression and interaction analysis models were applied. Results Final study population included 109,927 patients with a median age of 65 (IQR 52–76) years of whom 63,368 (58%) were males. 3,352 (3.1%) patients had significant TR. There were 2,384 (2%), 39,638 (36%), 43,086 (39%), and 24,700 (24%) individuals with underweight, normal weight, overweight, and obesity, respectively, with 3% of significant TR in each weight group. During a median follow-up of 4.7 (1.8–8.5) years 28,917 (26%) patients died. Interaction analysis of the multivariable model demonstrated that the association of significant TR with poor survival was significantly modified by BMI such that the association of significant TR with mortality differed across BMI groups (not significant for underweight groups, HR of 1.27 1.32 and 1.34 for normal weight, overweight and obesity, p |