Excitotoxicity is a process by which excitatory amino acids induce neuronal cell death. To what extent excitotoxicity is regulated by apoptotic molecules is currently unclear. We previously found that endonuclease G (EndoG) plays an important role in both normal apoptosis in vivo and in pre-implantation embryogenesis. To investigate whether EndoG participates in neuronal cell death, we compared EndoG expression and kainic acid (KA)-induced seizure behavior and excitotoxicity in EndoG+/- and wild-type mice. We found that EndoG expression in the hippocampus of EndoG+/- mice is reduced compared to that in the wild-type mice. The reduction of EndoG expression levels in the hippocampus did not result in altered KA-induced seizure severity in EndoG +/- mice compared to that in wild-type mice. However, both CA3 and CA1 pyramidal neurons in EndoG+/- mice are more resistant to KA-induced cell death than that in wild-type mice. These results indicate that reduced expression of EndoG in the hippocampi of EndoG+/- mice leads to resistance to excitotoxicity. © 2004 Elsevier Ireland Ltd. All rights reserved.