OBJECTIVE We evaluated endoscopic transnasal sphenoidotomy (ETNS) with or without ethmoidectomy in patients with inflammatory sphenoid sinus disease (ISSD). METHODS A retrospective review was conducted in 42 patients (17 males, 25 females; mean age 41 years; range 17 to 67 years) who underwent ETNS with (n=37) or without (n=5) ethmoidectomy for ISSD. The disase was staged according to our staging system based on computed tomography findings. RESULTS Postnasal drainage was the most common symptom (n=37, 88.1%). Chronic rhinosinusitis was accompanied by sinonasal polyps in 25 patients (59.5%). Five patients (11.9%) had isolated sphenoid disease and 16 patients (38.1%) had unilateral disease. Five patients (11.9%) had stage 1, 15 patients (35.7%) had stage 2, and 22 patients (52.4%) had stage 3 disease. Surgery involved 68 sides. Ethmoidectomy was used in 63 sides of 37 patients, eight of whom required a supplementary procedure. At least one complication was seen in eight patients (19%), including severe perioperative hemorrhage (n=2), early postoperative hemorrhage (n=2), minor injuries to the lamina papyracea (n=4), and synechiae (n=5). CONCLUSIONS In patients with isolated ISSD, the direct approach to the sphenoid sinus by ETNS without ethmoidectomy is a favorable technique, whereas ETNS with ethmoidectomy is necessary for patients with concurrent disease in other paranasal sinuses.