The aim of this study was to perform a comprehensive analysis of factors that affect procedural outcomes of transcatheter aortic valve replacement using the ACURATE neo prosthesis (Symetis/Boston, Ecublens, Switzerland). Predictors of procedural outcomes using the ACURATE neo prosthesis are poorly understood. A total of 500 patients underwent transfemoral aortic valve replacement with the ACURATE neo prosthesis. Device landing zone calcification was stratified as severe, moderate, or mild. Anatomic and procedural predictors of second-degree or greater paravalvular leakage and permanent pacemaker implantation were assessed. Post-procedural second-degree or greater paravalvular leakage was more frequent with increasing device landing zone calcification (mild 0.8% vs. moderate 5.0% vs. severe 13.0%; p < 0.001), whereas permanent pacemaker implantation was independent of device landing zone calcification. More severe periannular calcification (odds ratio OR: 1.007; 95% confidence interval CI: 1.003 to 1.010; p < 0.001), less oversizing (OR: 0.867; 95% CI: 0.773 to 0.971; p = 0.014), the presence of annular plaque protrusions (OR: 2.756; 95% CI: 1.138 to 6.670; p = 0.025), and aortic movement of the delivery system after full deployment (OR: 5.593; 95% CI: 1.299 to 24.076; p = 0.02), and sinotubular junction height (OR: 1.156; 95% CI: 1.007 to 1.328; p = 0.04) independently predicted second-degree or greater paravalvular leakage. Predictors of permanent pacemaker implantation were pre-existing right bundle branch block (OR: 3.122; 95% CI: 1.261 to 7.731; p = 0.01) and more oversizing (OR: 1.111; 95% CI: 1.009 to 1.222; p = 0.03). Successful transcatheter aortic valve replacement using the ACURATE neo device predominantly depends on careful patient selection with appropriate oversizing and taking into account the individual anatomy and calcium distribution of the aortic root.