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Background: Patient-specific computer simulation of transcatheter aortic valve replacement (TAVR) can provide unique insights in device-patient interaction. Aims: This study was to compare transcatheter aortic valve sealing behavior in patients with bicuspid aortic valves (BAV) and tricuspid aortic valves (TAV) through patient-specific computational modeling. Methods: Patient-specific computer simulation was retrospectively performed with FEops HEARTguide for TAVR patients. Simulation output was compared with postprocedural computed tomography and echocardiography to validate the accuracy. Skirt malapposition was defined by a distance larger than 1 mm based on the predicted device-patient interaction by quantifying the distance between the transcatheter heart valve (THV) skirt and the surrounding anatomical regions. Results: In total, 43 patients were included in the study. Predicted and observed THV frame deformation showed good correlation ( R 2 ≥ 0.90) for all analyzed measurements (maximum diameter, minimum diameter, area, and perimeter). The amount of predicted THV skirt malapposition was strongly linked with the echocardiographic grading of paravalvular leakage (PVL). More THV skirt malapposition was observed for BAV cases when compared to TAV cases (22.7 vs. 15.5%, p < 0.05). A detailed analysis of skirt malapposition showed a higher degree of malapposition in the interleaflet triangles section for BAV cases as compared to TAV patients (11.1 vs. 5.8%, p < 0.05). Conclusions: Patient-specific computer simulation of TAVR can accurately predict the behavior of the Venus A-valve. BAV patients are associated with more malapposition of the THV skirt as compared to TAV patients, and this is mainly driven by more malapposition in the interleaflet triangle region., Competing Interests: This study received funding from Venus Medtech. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Fan, Mortier, He, Zhu, Guo, Lin, Li, Jiang, Rocatello, Oliveira, Dezutter, Sondergaard and Wang.)