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The role of IL-12 in excitotoxic neurodegeneration of brain is largely unknown. To address this issue, we used the model of kainic acid (KA)-induced hippocampal injury in IL-12p35 knockout (KO) mice, a well-characterized model for human neurodegenerative diseases. After KA treatment, hippocampal neurodegeneration was significantly less severe in the IL-12p35 KO mice than in wild-type mice as demonstrated by reduced pathological changes and astrogliosis. One day after KA treatment, levels of F4/80 and CD86 expression on microglia were significantly lower in IL-12p35 KO mice than in wild-type mice analyzed by flow cytometry, indicating that IL-12p35 deficiency resulted in lower levels of microglial activation. Five days after KA treatment, CD86 expression on microglia of wild-type mice was still higher, whereas F4/80 expression in wild-type mice decreased and was similar to that in IL-12p35 KO mice. Because microglial activation is necessary for KA-induced neurodegeneration, the lower level of microglial activation in the absence of IL-12p35 may alleviate hippocampal injury in KO mice. In summary, this study indicates that IL-12 may play a critical role in excitotoxin-induced brain injury.