Aims: The conceptual framework of proportionate vs. disproportionate mitral regurgitation (MR) translates poorly to individual patients with heart failure (HF) and secondary MR. A novel index, the ratio of MR severity to left atrial volume (LAV), may identify patients with 'disproportionate' MR and a higher risk of events. The objectives, therefore, were to investigate the prognostic impact of MR severity to LAV ratio on outcomes among HF patients with severe secondary MR randomized to transcatheter edge-to-edge repair (TEER) with the MitraClip™ device plus guideline-directed medical therapy (GDMT) vs. GDMT alone in the COAPT trial., Methods and Results: The ratio of pre-procedural regurgitant volume (RVol) to LAV was calculated from baseline transthoracic echocardiograms. The primary endpoint was 2-year covariate-adjusted rate of HF hospitalization (HFH). Among 567 patients, the median RVol/LAV was 0.67 (interquartile range 0.48-0.91). In patients randomized to GDMT alone, lower RVol/LAV was independently associated with an increased 2-year risk of HFH (adjHR: 1.77; 95% CI: 1.20-2.63). RVol/LAV was a stronger predictor of adverse outcomes than RVol or LAV alone. Treatment with TEER plus GDMT compared with GDMT alone was associated with lower 2-year rates of HFH both in patients with low and high RVol/LAV (Pinteraction = 0.28). Baseline RVol/LAV ratio was unrelated to 2-year mortality, health status, or functional capacity in either treatment group., Conclusion: Low RVol/LAV ratio was an independent predictor of 2-year HFH in HF patients with severe MR treated with GDMT alone in the COAPT trial. TEER improved outcomes regardless of baseline RVol/LAV ratio., Clinical Trial Registration: Trial Name: Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial) (COAPT) ClinicalTrial.gov Identifier NCT01626079URL https://clinicaltrials.gov/ct2/show/NCT01626079., Competing Interests: Conflict of interest: A.C. has served as a consultant for Abbott and received speaker fees from Abbott and GE Healthcare. A.S. has served as a consultant and received consulting fees from NeoChord Inc. J.F.G. is the co-founder of Cephea Valve Technologies (Abbott). P.A.G. has received consulting fees from Abbott Vascular, Edwards Lifesciences, W.L. Gore, Medtronic, and 4C Medical and has received grant support from Abbott Vascular, Boston Scientific, Cardiovalve, Edwards Lifesciences, W.L. Gore, Medtronic, and Neochord. M.J.M. served as co-primary investigator for the PARTNER Trial for Edwards Lifesciences and COAPT trial for Abbott; served as study chair for the APOLLO trial for Medtronic; all activities unpaid. D.J.C. has received institutional research grants and consulting fees from Abbott, Edwards LifeSciences, Medtronic, and Boston Scientific. S.K. has received grants from Abbott, Boston Scientific, Edwards Lifesciences, and 4TECH; has been a consultant for Boston Scientific, Edwards Lifesciences, Medtronic, and 4TECH; and holds stock options in 4TECH. D.S.L. has received research grant support from Abbott, Boston Scientific, Corvia, Edwards, Medtronic, Trisol, and V Wave; consultant fees from Ancora, Philips, Valgen, and Venus. J.L. has received research grant support from AstraZeneca; consulting income from Abbott Vascular, Alleviant, AstraZeneca, Cordio, CVRx, Edwards Lifesciences, Boehringer Ingelheim, Merck, Medtronic, Vascular Dynamics, and V-Wave. J.B.’s institution has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific; he has also received speaker fees from Abbott Vascular. F.M.A. and N.J.W. report institutional contracts with Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. G.W.S. has received speaker honoraria from Medtronic, Pulnovo, Infraredx, and Abiomed; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. G.W.S.’s daughter is an employee at IQVIA. Institutional disclosure: G.W.S.’s employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc., Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. The other authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)