We reviewed the seizure frequencies of 38 patients with medically refractory epilepsy 6 weeks before (baseline) and 3 weeks after withdrawing their antiepileptic drugs (AEDs) for video-EEG monitoring. Seizure frequency during the first 3 weeks after restarting AEDs was diminished compared with baseline (P < 0.05). We found no correlation between seizure frequency and patient age, specific antiepileptic drugs, number of seizures during the video-EEG monitoring, number of days without AEDs, or partial vs total withdrawal of AEDs. Medication tachyphylaxis, functional tolerance, or long term post-ictal depression of the seizure threshold is hypothesized. The diminished seizure frequency after reinstitution of medications in four of five patients who did not have seizures during their hospitalization suggests that drug tachyphylaxis is a relevant mechanism.