The novel antiepileptic drugs levetiracetam (LEV) and topiramate (TPM) have been shown to influence pHi regulation when applied to hippocampal slices in clinically relevant concentrations. While LEV impaired Na+ -dependent Cl-/HCO3- transport, TPM has effects on both carbonic anhydrase and Na+-independent Cl-/HCO3- transport. Here we analysed effects of both drugs on pHi-regulation of human neocortical layer III tissue subsequent to ammonium prepulse (APP). Fluorescence measurements of pHi were carried out on BCECF-AM loaded slices of the gyrus temporalis medius 6–18h post surgery. Age of the patients ranged from 1–56 years (mean 27.6±18.8, n=13). pHi recovery after APP was largely inhibited by 500 mM DIDS but to a lesser extent by EIPA (50 mM), revealing a major though not exclusive role of bicarbonate-flux. Steady state pHi was slightly lowered by LEV (7/16) but rarely by TPM (2/14). pHi recovery after APP was often lowered by LEV (12/19) but to lesser extent by TPM (6/16). All effects on pHi were absent under Hepes-buffered conditions. Data show that especially LEV modulates transmembrane HCO3-transport as it does in animal models. Patient- or tissue-specific responses to LEV and TPM seem to exist at the level of neuronal circuits.