The role of perioperative antibiotic prophylaxis was investigated in 95 patients undergoing 100 clean-contaminated cranial base surgeries. A variety of antibiotic regimens were employed. Potential risk factors for local infection were analyzed. Seven patients (7%) developed infections at the surgical site (meningitis, intracranial abscess, cellulitis/abscess, and osteomyelitis). Antibiotic prophylaxis for 24 hours or less was associated with a significantly increased risk of infection (p less than 0.04). Prolonged antibiotic prophylaxis (greater than 48 hours) was not more efficacious than prophylaxis for 48 hours. The surgical approach, type of reconstruction, duration of surgery, and use of drains were not significantly correlated with wound infection. The risk of intracranial infection following cranial base surgery is low despite the presence of bacterial contamination intraoperatively. Broad-spectrum coverage of gram-positive and gram-negative organisms for at least 48 hours is recommended. Attention to surgical technique is important in preventing infectious complications.