The coverage of large surface areas of the brain for electrographic monitoring purposes necessitates a craniotomy to achieve comprehensive sampling. We undertook a review and prospective analysis over 3 years of 38 patients undergoing craniotomy for electrode implantation. The indication for invasive monitoring was to determine candidacy for resective surgery in patients whose seizure focus was not well localized by scalp electroencephalography and other noninvasive testing. Prophylactic cultures from the epidural space were obtained at electrode removal. There were five positive epidural cultures. All five patients went on to seizure-free status. Two positive cultures occurred in patients without obvious infection and who were not treated with antibiotics. Other complications included individual cases of atrial fibrillation, pulmonary edema, postoperative fever, and epidural hematoma. There was no mortality or permanent neurologic morbidity related to craniotomy for electrode placement. There was a 7.9% rate of clinical infection per patient and a 5.7% rate per craniotomy side. This study has identified several factors that significantly correlate with positive epidural culture results: > 100 electrodes, more than ten cables, more than 14 days of implantation, and more than one cable exit site.