The ACURATE neo transcatheter heart valve has demonstrated a balanced profile with low rates of permanent pacemaker implantation, low risk of coronary obstruction, and favorable hemodynamic properties whilst having an acceptable rate of ≥moderate paravalvular leakage (PVL). Here, we report in-hospital results and assess the learning curve for implantation of the ACURATE neo device in a large, single-center cohort. The cohort of this retrospective, observational study comprised 1,000 consecutive patients with severe aortic stenosis who underwent transfemoral transcatheter aortic valve implantation using the ACURATE neo prosthesis between May 2012 and December 2019. We determined procedural outcomes with emphasis on PVL and analyzed the learning curve. The median age was 81.9 years IQR 78.8; 85.1, and the Euroscore II was 4.2% IQR 2.7; 7.3. The rate of PVL ≥moderate measured by echocardiography at discharge was 3.7% (37 of 988). We observed a learning curve, with a decline in ≥moderate PVL from 6.7% in the first quartile to 0.8% in the last quartile, that was related to better patient selection, more oversizing, and consideration of the amount and distribution of aortic valve calcification. In this thus far largest single-center experience using the ACURATE neo prosthesis, we demonstrate that after completing a learning curve and observation of precepts that include patient selection, careful sizing, and procedural aspects, the rate of ≥moderate PVL may be reduced to <1%. •We observed a clear learning curve for the use of the ACURATE neo prosthesis.•Rates of ≥moderate paravalvular leakage declined from 7.4% to 0.8% in the last quartile.•A good patient selection and proper sizing are key for improved outcomes.