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Background: Lifetime treatment of aortic valve disease is a matter of increasing debate. Although the risks of a second aortic valve intervention are recognized, little attention has been given to the challenges of a third., Objectives: This study delves into the clinical characteristics, indications, and outcomes of patients undergoing 3 aortic valve interventions., Methods: The THIRD (THree aortIc Reinterventions for valve Disease) registry is a retrospective multicenter, international study of patients who underwent a third procedure on the aortic valve, either surgically or transcatheter-based. Patients undergoing 2 aortic procedures during the same hospital admission were excluded. Baseline characteristics, timing, and mode of bioprosthetic failure, sequence of the procedures, and clinical outcomes were adjudicated according to the Valve Academic Research Consortium criteria., Results: A total of 51 patients from 11 centers were enrolled in this study. Median follow-up time was 565 (314-1,560) days. Eighteen patients (35%) underwent surgical aortic valve replacement (SAVR), and 33 of 51 patients (65%) underwent transcatheter aortic valve replacement (TAVR) as the third intervention. Mean age was 69 ± 14 years, 20 of 51 patients (39%) were female. STS score was 5.0% (Q1-Q3: 3.3%-7.0%). In all TAVR cases, the indication for the first intervention was severe aortic stenosis, as was the indication in 31 of 45 (69%) of SAVR cases (33% bicuspid). The most prevalent procedure sequence was SAVR-SAVR-TAVR (19/51, 37%), followed by SAVR-SAVR-SAVR (10/51, 20%) and SAVR-TAVR-TAVR (10/51, 20%). TAVR-TAVR-TAVR was performed in 4 of 51 cases (8%). The primary indications for a third intervention included structural valve deterioration (SVD) (39/51, 76%), non-SVD (8/51, 16%), and endocarditis (2/51, 4%). Excluding patients with a mechanical prosthesis, predictors of SAVR as third intervention included a lower STS score (OR: 0.58; 95% CI: 0.34-0.98; P = 0.04) and the presence of moderate or severe prosthesis-patient mismatch (OR: 44.8; 95% CI: 2.41-122.00; P = 0.01). Thirty-day device success was 85% for TAVR and 94% for SAVR., Conclusions: In the THIRD registry, SVD emerged as the predominant indication for a third aortic valve procedure. The most frequent procedure sequence was SAVR-SAVR-TAVR, whereas TAVR-TAVR-TAVR was less common. Although the short-term outcomes in our selected cohort were favorable, further investigation is needed., Competing Interests: Funding Support and Author Disclosures Dr Tarantini has received honoraria for lectures/consulting from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, GADA. Dr Tang is a physician proctor, consultant, and advisory board member for Medtronic; is a consultant and advisory board member for Abbott Structural Heart; is an advisory board member for Boston Scientific and JenaValve; and has received speaker honoraria from Siemens Healthineers. Dr Kim has received personal fees from Abbott, Boston Scientific, Edwards Lifesciences, HI-D Imaging, Meril Life Sciences, and Shockwave Medical. Dr Pilgrim has received research, travel or educational grants to the institution without personal remuneration from Biotronik, Boston Scientific, Edwards Lifesciences, and ATSens; and has received speaker fees and consultancy fees to the institution from Biotronik, Boston Scientific, Edwards Lifesciences, Abbott, Medtronic, Biosensors, and Highlife. Dr Greenbaum has received institutional research support from Abbott Vascular, Ancora Heart, Edwards Lifesciences, Gore Medical, JenaValve, Medtronic, Polares Medical, Transmural Systems, and 4C Medical; has received consulting fees from Abbott Vascular, Edwards Lifesciences, and Medtronic; and has an equity interest in Transmural Systems. Dr Webb is a consultant for Edwards Lifesciences; and has received research funding from Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Makkar is a consultant for and received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr Franco is a proctor for Abbott Vascular and Edwards Lifesciences. Dr De Backer has received institutional research grants and consulting fees from Boston Scientific. Dr Fovino received consulting fees from Edwards Lifesciences and research grant from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)