Hyperpolarization-activated inward currents (I_H) have diverse functions in central neurones, including participation in oscillatory behaviour, stabilization of resting membrane potential and attenuation of temporal summation of EPSPs. The reduced magnitude of I_H in a rodent model of epilepsy (Strauss et al. 2004) and the augmentation of I_H by anticonvulsants (Poolos et al. 2002) further indicates that a reduced I_H may contribute to hyperexcitability in epileptic disorders. We further evaluated properties of I_H in human neocortical slices obtained from epilepsy surgery tissue (Kole et al. 1999). All patients (except one tumour case) suffered from pharmacoresistant epilepsy, i.e. had received various antiepileptic drugs. The methods were similar to those described previously (Deisz, 1999; Strauss et al. 2004). Hyperpolarising command potentials (2s, from -60 to -140 mV) evoked increasing inward currents, which were reduced by ZD7288 (n=6). The current densities, estimated from the currents at -140 mV and the membrane capacitance, averaged –2.6±1.7 pA/pF (mean±s.d.; n=236) in neurones from human cortex and –6.9±3.5 pA/pF (n=66) in rat cortical neurones (P<0.001; t test). The time constant of fast activation averaged 43.5±34.2 ms (n=264) in human neurones and 17.0±10.3 ms (n=69) in rat neurones (P<0.001). Application of 1 mM Ba²⁺ reduced instantaneous (Kir-type) currents of human neurones and increased I_H (control: -322±292 pA; Ba²⁺: -437±382 pA; n=65; P<0.001). The time constant of the fast activation (in Ba²⁺, at -140 mV) averaged 68.8± 38.7 ms in human (n=65) and 50.7±15.9 ms in rat neurones (n=27; P=0.0213). The voltage of half-maximal activation (V_1/2) of isolated I_H averaged -101.1±8.7 mV in human (n=8) and -92.5±4.7 mV in rat neurones (n=8; P=0.029). The magnitude of I_H in human neurones was unaffected by application of lamotrigine (100 µM) alone (n=22; P=0.67) or in the presence of 1 mM Ba²⁺ (n=46; P=0.76). In 41 tissues we estimated a burden of disease from the patients’ seizure frequencies (annual number of grand mal (GM) x years of epilepsy). We averaged the I_H densities of the neurones in control conditions from each tissue (2-11 neurones, average 4.8) and divided the tissues into two groups (below or above 15 GM). The tissues from patients with few GM (including the tumour case) had significantly higher average I_H densities (-3.2±1.4 pA/pF; n=21) compared to the group with many GM (-2.2±0.8 pA/pF; n=20; P=0.013). The group with few GM (average total count of GM 1.6) had the same average age (38.1±14.8 years) as the group with many GM (average total count 352 GM, average age: 38.1 ± 15.1 years, P=0.98). Our data indicate that specimen from patients with many seizures contain neurones with significantly lower average I_H densities. The difference in current magnitude, kinetics and V_1/2 values between rat and human epileptogenic cortex, may indicate a reduced contribution of HCN1 subunits in epileptogenic neocortices.