The vital neurovascular structures that border the sphenoid sinus make extensive sphenoid sinus surgery hazardous despite the advent of endoscopic sinus surgery (ESS). Computer-aided image-guided endoscopic sinus surgery (CAIGESS) has facilitated safer surgery by providing real-time analysis of complex, three-dimensional anatomic landmarks. We present 6 cases of atypical sphenoid disease, which greatly benefited from the unique superiority of CAIGESS in avoding surgical complications. Two cases of cerebrospinal-fluid (CSF) leak with concomitant meningoencephalocele of the sphenoid sinus were successfully managed with this technique. An inverting papilloma originating from the sphenoid sinus was successfully exenterated using CAIGESS. One patient, who experienced a lateral-rectus muscle palsy from sphenoid sinusitis, underwent successful sinusotomy with CAIGESS. Another patient, who had refractory left-sided sphenoid sinusitis despite 2 ESS procedures, was found to have an obliquely oriented intersinus septum which misled the previous surgeons to enter mistakenly the contralateral sphenoid sinus. CAIGESS allowed accurate identification and removal of the intersinus septum and relief of the sinusitis. Finally, a sphenoid-sinus mucocele that developed after a prior pituitary surgery was safely decompressed with CAIGESS. This surgical approach offers a new and effective adjunct to ESS in selected revision or difficult sinus cases and has proven invaluable in complicated sphenoid cases where the surrounding neurovascular anatomy could otherwise be jeopardized.