The effect of propofol on the electroencephalogram (EEG) in patients with epilepsy is still unclear. Case reports with electroencephalographic documentation highlight pro- and anticonvulsant effects and beta activation of the EEG. This prospective study sought to determine the effect of propofol in 17 patients undergoing cortical resection for intractable epilepsy. Each patient received 2 mg/kg of propofol intravenously and the EEG was recorded from chronically implanted subdural electrodes placed during a previous craniotomy. Frequency of interictal spikes, time to burst suppression, and appearance of beta activation were recorded. The median frequency of interictal spikes decreased significantly from 2 spikes/min before to 0 spikes/min after propofol (P = 0.001). Seizure activity did not increase after propofol. Profound burst suppression and an increase in beta activity were noted consistently. The use of propofol in patients with epilepsy seems to be safe but may interfere with the recording of EEG spikes.