Objective: To highlight concepts critical to achieving successful repair and avoiding intracranial complications in the treatment of cerebrospinal fluid (CSF) leaks from the lateral recess of the sphenoid sinus (LRS). Design: Outcomes study. Setting: Tertiary referral university hospital. Patients: Eleven patients with LRS CSF leaks from June 2008 to June 2010. Interventions: Endoscopic transpterygoid approach and multilayer repair of skull base defect in the LRS. Main Outcome Measures: Recurrence, graft techniques, postoperative intracranial pressure (ICP), and use of ventriculoperitoneal (VP) shunt. Results: Thirteen CSF leaks originating in the LRS were surgically repaired in 11 patients; 2 patients required bilateral leak repair. The endoscopic transpterygoid approach was used in 12 of 13 repairs. Eight patients had failed attempts at repair prior to presentation (4 endoscopic sphenoidotomies and 4middle cranial fossa [MCF] approaches). One patient presented with a temporal lobe abscess following hydroxyapatite "obliteration" to seal off the LRS. This required a combined MCF/transpterygoid approach to drain the abscess, remove the encephalocele and hydroxyapatite, and seal the skull base defect. In 2 cases, the LRS was left patent owing to concerns of inadequate mucosal extirpation. The median duration of follow- up was 10.8 months (range, 2-29 months). One patient experienced a failure (2 months after repair), which was successfully sealed on the second attempt. Postoperatively, 5 patients required VP shunts, and 5 were maintained on acetazolamide for elevated ICP (average, 26.7 cm H 2O in 8 patients; presumed elevated in 2 patients). Conclusions: The current study demonstrated a 92% success rate using the endoscopic transpterygoid approach for LRS skull base defects providing support for routine use in the treatment algorithm. Poor outcomes were observed with previous surgical attempts to obstruct the LRS without repairing the skull base defect.