Background: Cerebrospinal fluid rhinorrhea in the sphenoid sinus lateral recess is a rare occurrence and poses unique challenges due to limited surgical access for surgical repair. Objective: To report our experience of surgical repair of cerebrospinal fluid rhinorrhea in the sphenoid sinus lateral recess through an endoscopic endonasal transpterygoid approach with obliteration of the lateral recess. To evaluate the efficiency of this surgical procedure. Methods: A retrospective study. Twelve cases with cerebrospinal fluid rhinorrhea in the sphenoid sinus lateral recess were reviewed. Assisted by image-guided navigation, cerebrospinal fluid rhinorrhea was repaired through an endoscopic endonasal transpterygoid approach, with obliteration of the lateral recess. Complications and recurrence were recorded. Medical photographs were used. Results: This surgical approach provided a relatively spacious corridor to dissect the sphenoid sinus lateral recess and do postoperative surveillance. The repair area completely healed in 3 months after surgery. Cerebrospinal fluid rhinorrhea in the sphenoid sinus lateral recess was successfully repaired on the first attempt in all cases (100%). No main complications or recurrence was observed during a mean follow-up time of 40.3 months. Conclusion: The endoscopic endonasal transpterygoid approach gives appropriate access for the treatment of spontaneous cerebrospinal fluid rhinorrhea in the sphenoid sinus lateral recess. Multilayer reconstruction of a skull base defect with obliteration of the lateral recess is a reliable and simple method.