Objective: The cranio-orbitozygomatic (COZ) approach improves the surgical exposure by providing the shortest possible route to the lesion. We discussed the microsurgical anatomy of the region and described the steps for a safe COZ approach. Methods: The COZ approach and its modifications were performed in 21 cases between November 2004 - December 2005 for lesions involving the skull base and brainstem. We analyzed each of the operative procedures retrospectively and discussed the technical difficulties in the light of the microsurgical anatomy of the region. Results: The two-piece COZ approach provides the removal of a considerable amount of orbital roof and lateral wall and the craniotomy can safely be extended into the superolateral border of the superior orbital fissure. The sequences of the orbital and zygomatic osteotomies can be standardized regardless of the exposure of the inferior orbital fissure, which depends on the distance between its anterolateral edge and the frontozygomatic suture. The orbitopterional modification of the COZ, in which the removal of the zygoma is omitted, can be used when the lesion is located primarily anteriorly and when the subtemporal approach is unnecessary. Conclusions: The technical difficulties and complications related to the COZ approach can be minimized by understanding the regional microsurgical anatomy in relation to the orbital and zygomatic osteotomies, all of which should be performed in a rational fashion.