Background: An inferoposterior transseptal puncture (TSP) is generally recommended for percutaneous left atrial appendage (LAA) closure. However, the LAA is a highly variable anatomical structure. This may have an impact on the preferred TSP site. Aims: This study aimed to determine the optimal TSP site for percutaneous LAA closure in different LAA morphologies. Methods: In this prospective study, 182 patients undergoing percutaneous LAA closure were included. The spatial relationship of the LAA to the fossa ovalis and its consequence for TSP was assessed at preprocedural cardiac computed tomography (CCT). Results: Based on CCT analysis, it was predicted that coaxial alignment between the delivery sheath and the LAA would be obtained by an inferoposterior, inferocentral, or inferoanterior TSP in 75%, 16% and 8% of cases, respectively. This was also confirmed by procedural LAA angiogram in 175 cases (96%) with <30° angle between the delivery sheath and the LAA central axis. Multivariate logistic regression analysis identified reverse chicken wing LAA (odds ratio [OR] 6.36 [1.85-29.3]; p=0.005) and posterior bending of the proximal LAA (OR 17.2 [3.3-96.2]; p<0.001) as independent predictors of a central or anterior TSP - this to increase the chance of obtaining coaxial alignment between the delivery sheath and the LAA. Conclusions: An inferoposterior TSP is recommended in the majority of percutaneous LAA closure procedures in order to obtain coaxial alignment between the delivery sheath and the LAA. An inferior but more central/anterior TSP should be recommended in case of a reverse chicken wing LAA or posterior bending of the proximal LAA, which occurs in 20-25% of cases.