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BACKGROUND Endoscopic transorbital approach (ETOA) has been proposed as a minimally invasive technique for the treatment of skull base lesions located around mesial temporal lobe (MTL), mostly extra-axial pathology. OBJECTIVE To explore the feasibility of ETOA in accessing intraparenchymal MTL with cadaveric specimens and describe our initial clinical experience of ETOA for intra-axial lesions in MTL. METHODS Anatomic dissections were performed in 4 adult cadaveric heads using a 0° endoscope. First, a stepwise anatomical investigation of ETOA to intraparenchymal MTL was explored. Then, ETOA was applied clinically for 7 patients with intra-axial lesions in MTL, predominantly high-grade gliomas (HGGs) and low-grade gliomas (LGGs). RESULTS The extradural stage of ETOA entailed a superior eyelid incision followed by orbital retraction, drilling of orbital roof, greater and lesser wing of sphenoid bone, and cutting of the meningo-orbital band. For the intradural stage, the brain tissue medial to the occipito-temporal gyrus was aspirated until the temporal horn was opened. The structures of MTL could be aspirated selectively in a subpial manner without injury to the neurovascular structures of the ambient and sylvian cisterns, and the lateral neocortex. After cadaveric validation, ETOA was successfully performed for 4 patients with HGGs and 3 patients with LGGs. Gross total resection was achieved in 6 patients (85.7%) without significant surgical morbidities including visual field deficits. CONCLUSION ETOA provides a logical line of access for intra-axial lesions in MTL. The safe and natural surgical trajectory of ETOA can spare brain retraction, neurovascular injury, and disruption of the lateral neocortex.