The aim of this study was to evaluate outcomes of transcatheter mitral valve replacement (TMVR) with transfemoral access in patients at prohibitive or high surgical risk. Prohibitive surgical risk may preclude mitral valve replacement surgery in some patients. The investigational Intrepid TMVR system has previously been evaluated using transapical access for delivery of a self-expanding bioprosthetic valve. This prospective, multicenter, nonrandomized early feasibility study evaluated the safety and performance of the Intrepid valve using transfemoral access enabling transseptal delivery in patients with moderate to severe or severe symptomatic mitral regurgitation at high surgical risk. Candidacy was determined by heart teams, with approval by a central screening committee. Echocardiographic data were evaluated by an independent core laboratory. Clinical events were adjudicated by a clinical events committee. Fifteen patients were enrolled at 6 sites from February 2020 to May 2021. The median age was 80 years, and median Society of Thoracic Surgeons Predicted Risk of Mortality was 4.7%; 87% of patients were men, and 53% had undergone prior sternotomy. Fourteen implants were successful. One patient was converted to surgery during the index procedure. Patients stayed a median of 5days postprocedure. There were 6 access site bleeds (40%) and 11 iatrogenic atrial septal defect closures (73%). At 30days, there were no deaths, strokes, or reinterventions. All patients undergoing implantation had trace or no valvular or paravalvular mitral regurgitation, and the mean gradient was 4.7 mm Hg (IQR:3.0-6.7 mm Hg). Thirty-day results from the Intrepid transfemoral TMVR early feasibility study demonstrate excellent valve function and no mortality or stroke. Additional patients and longer follow-up are needed to confirm thesefindings. ([The Early Feasibility Study of the Intrepid™ TMVR Transseptal System]; NCT02322840).