Voltage-dependent sodium channels consist of a pore-forming alpha-subunit and regulatory beta-subunits. Alterations in these channels have been implicated in temporal lobe epilepsy (TLE) and several genetic epilepsy syndromes. Recently we identified Na(v)beta3 as a TLE-regulated gene. Here we performed a detailed analysis of the hippocampal expression of Na(v)beta3 in TLE patients with hippocampal sclerosis (HS) and without HS (non-HS) and compared expression with autopsy controls (ACs). Immunoblot analysis showed that Na(v)beta3 levels were dramatically reduced in the hippocampus, but not in the cortex of non-HS patients when compared to HS patients. This was confirmed by immunohistochemistry showing reduced Na(v)beta3 expression in all principal neurons of the hippocampus proper. Sequence analysis revealed no Na(v)beta3 mutations. The functional consequences of the reduced Na(v)beta3 expression in non-HS patients are unknown. Altered Na(v)beta3 expression might influence microcircuitry in the hippocampus, affecting excitability and contributing to epileptogenesis in non-HS patients. Further experiments are required to elucidate these functional possibilities.