The aim of this proof-of-principle study is to validate the accuracy of fusion imaging for percutaneous transapical access (TA). Structural heart disease interventions, including TA, are commonly obtained under fluoroscopic guidance, which lacks important spatial information. Computed tomographic angiography (CTA)-fluoroscopy fusion imaging can provide the 3-dimensional information necessary for improved accuracy in planning and guidance of these interventions. Twenty consecutive patients scheduled for percutaneous left ventricular puncture and device closure using CTA-fluoroscopy fusion guidance were prospectively recruited. The HeartNavigator software (Philips Healthcare, Best, the Netherlands) was used to landmark the left ventricular epicardium for TA (planned puncture site [PPS]). The PPS landmark was compared with the position of the TA closure device on post-procedure CTA (actual puncture site). The distance between the PPS and actual puncture site was calculated from 2 fixed reference points (left main ostium and mitral prosthesis center) in 3 planes (x, y, and z). The distance from the left anterior descending artery at the same z-plane was also assessed. TA-related complications associated with fusion imaging were recorded. The median (interquartile range [IQR]) TA distance difference between the PPS and actual puncture site from the referenced left main ostium and mitral prosthesis center was 5.00 mm (IQR: 1.98 to 12.64 mm) and 3.27 mm (IQR: 1.88 to 11.24 mm) in the x-plane, 4.48 mm (IQR: 1.98 to 13.08 mm) and 4.00 mm (IQR: 1.62 to 11.86 mm) in the y-plane, and 5.57 mm (IQR: 3.89 to 13.62 mm) and 4.96 mm (IQR: 1.92 to 11.76 mm) in the z-plane. The mean TA distance to the left anterior descending artery was 15.5 ± 7.8 mm and 22.7 ± 13.7 mm in the x- and y-planes. No TA-related complications were identified, including evidence of coronary artery laceration. With the use of CTA-fluoroscopy fusion imaging to guide TA, the actual puncture site can be approximated near the PPS. Moreover, fusion imaging can help maintain an adequate access distance from the left anterior descending artery, thereby, potentially reducing TA-related complications.