Efficacy and tolerability of levetiracetam (LEV) as perioperative seizure prophylaxis in supratentorial brain tumor patients were retrospectively studied. Between February 2007 and April 2009 in a single institution, 78 patients with primary or secondary supratentorial brain tumors [40 female, 38 male; mean age 57 years, from 27 to 89 years; gliomas in 42 patients (53.8%), brain metastases in 17 (21.8%), meningiomas in 16 (20.5%), 1 primary central nervous system (CNS) lymphoma patient, and 2 patients with radiation necrosis] received between 1,000 mg and 3,000 mg LEV perioperatively. Preoperatively, 30 patients had experienced seizures (38.5%), most commonly glioma patients (47.6%), but also meningioma patients (31.3%) or patients with brain metastases (23.5%). No more seizures occurred in patients receiving 1-3 g LEV preoperatively. Within the first week postoperatively, a single seizure occurred in two patients (2.6%). At the end of the follow-up period (mean 10.5 months, range 0-31 months), 71 of the 78 patients (91%) were seizure free and 21 (26%) patients were not taking antiepileptic drugs. We observed side-effects in five patients (6.4%), including non-tumor-associated progressive somnolence in three patients (1.5 g, 1.5 g, and 2 g LEV daily) and reactive psychosis in two patients (1 and 1.5 g LEV daily), regressing after dose reduction. Perioperative LEV in supratentorial brain tumor patients was well tolerated. Compared with the literature, it resulted in low (2.6%) [corrected] seizure frequency in the early postoperative period. Additionally, its advantage of lacking cytochrome P450 enzyme induction allowed early initiation of effective postoperative chemotherapy in malignant glioma patients.