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 β 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 β 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 β 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.