BACKGROUND: Older adults with comorbidities who are at extreme risk for surgical aortic valve replacement may be appropriate candidates for transcatheter aortic valve replacement (TAVR). We present the 5-year clinical, echocardiographic, and health status outcomes of such patients treated with CoreValve self-expanding supra-annular TAVR. METHODS: The CoreValve US Extreme Risk Pivotal Trial was a prospective, nonrandomized, single-arm clinical trial of TAVR at 41 sites in the United States. The primary outcome was all-cause mortality or major stroke. Secondary outcomes included echocardiographic parameters and patient-reported health status, assessed with the Kansas City Cardiomyopathy Questionnaire. RESULTS: Between February 2011 and August 2012, 639 patients with severe aortic stenosis at extreme surgical risk underwent attempted TAVR (mean age 82.8±8.4 years, 53% women, mean Society of Thoracic Surgeons Predicted Risk of Mortality 10.4±5.6%, 77% iliofemoral access). The 5-year Kaplan-Meier rate of death or major stroke was 72.6% ([95% CI, 68.4%–76.7%]; death 71.6%, major stroke 11.5%), with no significant differences according to access site. Among patients who survived 5 years, mean transvalvular gradient was 7.5±5.9 mm Hg, and 3.1% had moderate or severe aortic regurgitation. Health status measures improved significantly by 1 month after TAVR through 1 year (mean change in Kansas City Cardiomyopathy Questionnaire–Overall Summary score 24.8 points [95% CI, 22.4–27.2]). Beyond 1 year, the Kansas City Cardiomyopathy Questionnaire–Overall Summary score decreased gradually but remained significantly improved from pre-TAVR through 5 years of follow-up among surviving patients (mean change from baseline, 14.3 points [95% CI, 10.7–17.9]). CONCLUSIONS: Patients with severe aortic stenosis at extreme surgical risk who are treated with self-expanding supra-annular TAVR have high 5-year mortality. However, the short-term benefits of TAVR in terms of valve hemodynamics and quality of life are mostly preserved among surviving patients at 5 years, thereby supporting the continued use of TAVR in these challenging patients. REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT01240902.