Background: Sphenoid sinus is surrounded by several important structures. Sphenoid sinuses are the most inaccessible paranasal sinuses and are surrounded by significant anatomical structures such as the orbit and its contents, cavernous sinus and internal carotid artery (ICA), and the anterior cranial fossa. The different routes to the sella include transethmoidal, transnasal, trans-septal, whether microscopic or endoscopic; ultimately pass through the sphenoid sinus to reach the sella. Complications such as arterial hemorrhage, visual loss, and extra-ocular palsies occurring in the course of endoscopic sinus surgeries or transsphenoidal pituitary procedures can be attributed to the proximity of carotid artery and cranial nerves to the sphenoid sinus. Objective: To study the important structures in the sphenoid sinus and find anatomical variations to guide otorhinolaryngologists to avoid injury of the vital structures during their procedures. Patients and methods: This study comprised 100 patients complaining of sinonasal attending ENT Department at Al-Azhar University Hospital (Cairo) from October 2018 to October 2020. All patients were subjected to full history taking, clinical and endoscopic examinations, CT scan and MRI. Results: We found pneumatization of pterygoid process (PP), anterior clinoid process (ACP) and greater wing of sphenoid (GWS) in 30%, 16% and 30% of patients. We found protrusion of anterior clinoid process (ACP), optic nerve (ON), maxillary nerve (MN) and vidian nerve (VN) in 40%, 36%, 25% and 28% of patients and dehiscence of them in 30%, 31%, 14% and 37% of patients. There was a significant association between ACP pneumatization and ICA protrusion, ACP pneumatization and ON protrusion, PP pneumatization and VN protrusion, and GWS pneumatization and MN protrusion. There were significant associations between GWS pneumatization and MN protrusion and between PP pneumatization and VN protrusion. Conclusion: Coronal CT screening should be used in the pre-surgical evaluation of patients under consideration of endoscopic sphenoid sinus surgery to minimize perioperative neural and vascular injury.