BACKGROUND: The clinical and molecular effects of antiepileptic drugs (AEDs) have been extensively investigated. Much less is known about their effects on human electrophysiology. METHODS: Topographic analysis in the frequency domain has been used to analyze 104 electroencephalogram (EEG) epochs of 52 patients presenting with first-ever generalized seizure, with normal MRI and EEG. Patients were treated with valproate, arbamazepine, or lamotrigine in monotherapy (each group n = 13). Thirteen patients without medication served as a control group. RESULTS: Carbamazepine and lamotrigine, both sodium-channel modulators, altered brain topography in the gamma range in the same frequency bands (50-60 Hz). Valproate, which has multiple actions on sodium and calcium channels as well as GABA turnover, modified brain topography in the low gamma range (30-40 Hz). No such changes were found in the control group. For all AEDs, the neural generators were shifted more anteriorly in medial temporal through to inferior frontal regions. CONCLUSION: Decreased gamma-power and anterior shift of neural generators after AED introduction reflect AED influence on human electrophysiology.