The human DLG3 gene encodes the synapse-associated protein 102 (SAP102), which is concentrated in the postsynaptic densities of excitatory synapses and involved in receptor-mediated synaptic transmission via binding to the NR2B subunit of the NMDA receptor. In this study, we investigated the expression and cellular distribution of the DLG3/SAP102 protein in human epileptic cortex. Tissue microarrays of a large number of specimens from patients operated for medically intractable epilepsy were used for immunohistochemical screening with anti-DLG3 antibody. The cellular distribution of the protein was further investigated in samples of malformations of cortical development, and the amount of DLG3 protein in the total homogenate and in the postsynaptic membrane fraction of these samples was quantified by Western blot. We found a strictly neuronal expression of DLG3/SAP102 in epileptogenic cortex as well as in non-epileptic human cortex used for control. In focal cortical dysplasia and tuberous sclerosis complex, the protein was expressed in most neurons including dysplastic neurons, but not in giant cells. Increased expression of DLG3 protein was observed in the postsynaptic membrane fraction of patients with focal cortical dysplasia. Double-labeling experiments confirmed the exclusive neuronal character of the DLG3 expressing cells and the co-localization of the DLG3 protein with the NR2B subunit. Our results suggest a putative role for DLG3/SAP102 in cortical hyperexcitability and epileptogenicity of malformations of cortical development.