This study analyzed the causes of sphenoid sinus (SS) infection (SSI) following endoscopic transsphenoidal skull base surgery and determined appropriate treatment methods.This study included 31 cases of secondary SSI following the endoscopic transsphenoidal approach (ETSA; SSI group) and 246 cases without SSI (non-SSI group). Data collected included post-ETSA pathological results, types of artificial skull base reconstruction materials, and SS patency. For the SSI group, data included time from ETSA to symptom onset, endoscopic and imaging findings, intraoperative conditions during the second surgery, and changes in visual analog scale (VAS) scores.The incidence of secondary SSI was 11.19%. In the SSI group, 26 patients (83.87%) reported headaches, and 24 (77.42%) had stenosis or closure of the SS ostium (SSO). The non-SSI group reported no symptoms, and 236 patients (95.93%) had well-opened SSOs. Centripetal hyperosteogeny (CHO) in the SS walls was observed in 20 patients (64.5%) in the SSI group. Absorbable materials were used in five cases (16.13%) and 215 cases (87.40%) in the SSI and non-SSI groups, respectively, while non-absorbable materials were used in 24 cases (77.42%) and 20 cases (8.13%), respectively. SSI risk was 9.42 times higher with non-absorbable synthetic materials. VAS scores for SSI symptoms and Lund-Kennedy scores significantly decreased at 3 and 12 months post-second surgery.Secondary SSI after ETSA can cause persistent symptoms. Non-absorbable synthetic repair materials should be avoided to prevent secondary SSI. Extended sphenoidectomy and removal of artificial materials can lead to rapid resolution of SSI symptoms.4.© 2024 The Author(s). Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.