Background: Large endoscopic skull-base resections often result in extensive postoperative pneumocephalus secondary to copious evacuation of cerebrospinal fluid (CSF) during the procedures. Replacing CSF lost during craniotomy with saline is a common technique in neurosurgery, but is difficult after extensive transnasal resection of the anterior cranial base because direct transnasal CSF augmentation will escape until the skull base reconstruction is sealed. The present study evaluated the effectiveness of intraoperative CSF volume replacement via lumbar drains on improving postoperative outcomes. Methods: Ten large endoscopic anterior skull-base resections (>2.5 cm) were performed from 2008 to 2011. Sellar, parasellar, and transplanum resections were excluded. Etiologies included esthesioneuroblastoma (2), squamous cell carcinoma (2), intracranial dermoid (2), adenocarcinoma (1), adenoid cystic carcinoma (1), melanoma (1), and meningioma (1). Six patients were administered preservative-free normal saline via lumbar drain during skull-base reconstruction. Data collected included volume of postoperative pneumocephalus, intravenous pain medicine requirements 24 hours after surgery, and length of hospital stay. Results: Volume of pneumocephalus (4.78 cm vs 12.8 cm 3, p = 0.04) and length of hospital stay (2.17 days vs 8.5 days, p = 0.03) were significantly decreased in the normal saline volume replacement group. Average intravenous pain medication requirements were reduced in the first 24 hours postoperatively (8 mg morphine vs 14 mg morphine, p = 0.25), but did not reach statistical significance. Conclusion: Evacuation of intracranial air by transthecal administration of saline during reconstruction of large anterior cranial base defects was an effective technique to decrease postoperative pneumocephalus and length of hospital stay. Further evaluation is warranted. © 2012 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.