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Background: Sphenoid sinus is the most inaccessible paranasal sinus, enclosed within the sphenoid bone and intimately related to numerous vital neural and vascular structures. Anatomic variation of the sphenoid sinus is well documented and may complicate surgery in such a place. Objective: To outline the surgically risky anatomic variants of the sphenoid sinus as well as the variable relationships between the sinus and related neurovascular structures, for the safe removal of intrasphenoid and pituitary lesions. Materials and Methods: We undertook a prospective review of 300 paranasal sinus CT scans of Libyan patients; coronal CT scans were obtained by special parameter techniques. We assessed pneumatization of pterygoid process (PP), anterior clinoid process (ACP), and greater wing of sphenoid (GWS); we also examined protrusion and dehiscence of internal carotid artery (ICA), optic nerve (ON), maxillary nerve (MN), and vidian nerve (VN) into the sphenoid sinus cavity. Results: Pneumatization of PP, ACP, and GWS were seen in 87 (29%), 46 (15.3%), and 60 patients (20%), respectively. Protrusion of ICA, ON, MN, and VN were noticed in 123 (41%), 107 (35.6%), 73 (24.3%), and 81 patients (27%), respectively; dehiscence of these structures was encountered in 90 (30%), 92 (30.6%), 39 (13%), and 111 patients (37%), respectively. Statistically, there was a highly significant association between ACP pneumatization and ICA protrusion, ACP pneumatization and ON protrusion, PP pneumatization and VN protrusion; and GWS pneumatization and MN protrusion (p-value < 0.001). Conclusion: The sphenoid sinus is highly variable; this variability necessitates a comprehensive understanding of the regional sphenoid sinus anatomy by a detailed CT scan sinus examination before surgery in and around the sinus. This study indicates the possibility of a racial anatomical variation of the sphenoid sinus in the Libyan population.