Background: Acetazolamide has become a standard treatment for cerebrospinal fluid (CSF) leaks associated with intracranial hypertension. The purpose of the current study was to evaluate the effectiveness of acetazolamide at decreasing elevated CSF pressure in this patient population. Methods: Prospective evaluation and data collection of high intracranial pressure CSF leaks was performed. Subjects underwent CSF diversion and postoperative assessment of pressure changes via a standard protocol. Lumbar drains or ventriculostomies were clamped on postoperative day 2 for 4 hours prior to assessment with a manometer. Acetazolamide (500 mg) was administered orally immediately following the recording and CSF pressure was measured after 4 hours. Data regarding demographics, etiology of CSF leak, body mass index (BMI), location and size of defect, and clinical follow-up were also collected. Results: Thirty-six patients (average age 50 years) with 42 CSF leaks (39 spontaneous, 3 traumatic) and an average BMI of 36.1 were evaluated. Success rate of primary repair was 94.4%, but all patients were effectively sealed with subsequent endoscopic reconstruction (average 80 weeks follow-up). Intracranial pressure (cm H2O) via lumbar puncture or ventriculostomy (n = 2) after clamping was 32.0 ± 7.4. Administration of acetazolamide significantly decreased intracranial pressure to 21.9 ± 7.5 in the 4-6 hour time frame studied (p < 0.0001). Conclusion: This study provides some of the first direct evidence of decreased intracranial pressure associated with the oral administration of acetazolamide. In combination with the excellent endoscopic repair outcomes noted in a high risk population, this evidence supports the routine use of acetazolamide in patients with high intracranial pressure CSF leaks. © 2013 ARS-AAOA, LLC.