The aim of this study was to develop a less invasive trans-septal approach for the endoscopic management of sphenoid sinus lesions. We performed a septal-assisted surgical procedure for endoscopic sphenoidectomy in 38 patients with isolated or combined sphenoidal sinus lesions, including fungal balls, mucoceles, purulent cystic sphenoidal sinusitis, etc. The posterior portion of the nasal septum became flexible after removal of the vomer and the sphenoidal rostrum. The superior portion of the common meatus was expanded to accommodate the endoscope after the septum was repositioned contra-laterally. The lesions were individually managed through the enlarged ostiums while damage to the mucosa of the front sphenoidal wall was avoided. All the procedures were completed successfully without intraoperative complications, and the bony ostiums were identified easily and enlarged accurately. During the follow-up period of 16 weeks to 2 years, no re-atresia or restenosis was observed. The recurrence rate was 0. No postoperative complications were recorded. All the responses from the patients were satisfactory. It was concluded that endoscopic sphenoidectomy assisted by trans-septal approach is a feasible, safe, effective and minimally invasive approach for selected cases with unilateral or bilateral lesions in the sphenoid sinuses.