Background: Transcatheter aortic valve replacement (TAVR) with the ACURATE neo device has been associated with a non-negligible incidence of paravalvular aortic regurgitation (AR). The new-generation ACURATE neo2 has been designed to mitigate this limitation. Aims: The aim of the study was to compare TAVR with the ACURATE neo and neo2 devices. Methods: The NEOPRO and NEOPRO-2 registries retrospectively included patients undergoing transfemoral TAVR with self-expanding valves at 24 and 20 centres, respectively. Patients receiving the ACURATE neo and neo2 devices (from January 2012 to December 2021) were included in this study. Predischarge and 30-day VARC–3 defined outcomes were evaluated. The primary endpoint was predischarge moderate or severe paravalvular AR. Subgroup analyses per degree of aortic valve calcification were performed. Results: A total of 2,026 patients (neo: 1,263, neo2: 763) were included. Predischarge moderate or severe paravalvular AR was less frequent for the neo2 group (2% vs 5%; p<0.001), resulting in higher VARC-3 intended valve performance (96% vs 90%; p<0.001). Furthermore, more patients receiving the neo2 had none/trace paravalvular AR (59% vs 38%; p<0.001). The reduction in paravalvular AR with neo2 was mainly observed with heavy aortic valve calcification. New pacemaker implantation and VARC-3 technical and device success rates were similar between the 2 groups; there were more frequent vascular and bleeding complications for the neo device. Similar 1-year survival was detected after TAVR (neo2: 90% vs neo: 87%; p=0.14). Conclusions: TAVR with the ACURATE neo2 device was associated with a lower prevalence of moderate or severe paravalvular AR and more patients with none/trace paravalvular AR. This difference was particularly evident with heavy aortic valve calcification.