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Background: Anatomical knowledge of the zygomatico-orbital artery and its most relevant clinical applications is essential for ensuring the safety of filler injection into the temporal region. The purpose of this study was to provide the precise position, detailed course, and relationship with surrounding structures of the zygomatico-orbital artery. Methods: Fifty-eight patients who underwent head contrast-enhanced three-dimensional computed tomography and 10 fresh frozen cadavers were investigated. Results: The zygomatico-orbital artery was identified in 93 percent of the samples in this work. Ninety-four percent of the zygomatico-orbital arteries derived directly from the superficial temporal artery, and the remaining arteries started from the frontal branch of the superficial temporal artery. According to the origin of the zygomatico-orbital artery, it was classified into type I and type II. Type I arteries were then classified into three subtypes. The trunk of the zygomatico-orbital artery was located between the deep temporal fascia and the superficial temporal fascia. Deep branches of the zygomatico-orbital artery pierced the superficial layer of the deep temporal fascia. The zygomatico-orbital artery originated from 11.3 mm in front of the midpoint of the apex of the tragus, and most of its trunks were located less than 20.0 mm above the zygomatic arch. The mean diameter of the zygomatico-orbital artery was 1.2 ± 0.2 mm. There were extensive anastomoses between the zygomatico-orbital artery and various periorbital arteries at the lateral orbital rim. Conclusion: The precise anatomical knowledge of the zygomatico-orbital artery described in this study could be helpful for cosmetic physicians for improving the safety of temporal augmentation.