Zonisamide (ZNS) is an anticonvulsant drug with numerous mechanism of action. It is currently assumed that an increase of serotonin levels, blockage of T-type Ca2+- and also of sodium channels are among its major anticonvulsant mechanisms. However, like other sulfonamide derivates ZNS also inhibits carbonic anhydrase subtypes. We therefore investigated its effects on the intracellular pH (pHi) and also on epileptic seizure models in which lowering the pHi acts anti-epileptic. Experiments were carried out on hippocampal slices from adult guinea pigs under bicarbonate-buffered conditions. ZNS changed neither neuronal steady state pHi(n=8) nor pHi regulation subsequent to an ammonium prepulse (n=6) of BCECF-AM loaded hippocampal neurons. ZNS had also no effect on the frequency of xanthine derivative-induced epilepsy (n=4), although in this model epileptic bursting is reduced by hypercapnia, intracellular acidosis, or serotonin (50 mM). Nevertheless, in 4-aminopyridine-treated (50 mM) slices 25–50mM ZNS shortened epileptiform bursts and reversibly lowered the frequency of action potentials and bursts in 7 out of 10 cases. We conclude that ZNS does not influence epileptiform activity via changes of intracellular pH. The obvious discrepancy of the effect of ZNS applied to various epileptic model systems deserves further attention.