The mechanism underlying the pathology of Huntington's disease (HD) is unknown, although there is substantial evidence supporting a role for excitotoxicity. The discovery of abnormal aggregations of protein in the brains of patients with HD, as well as in the brains of transgenic mice modeling this disease, has led to the suggestion that these "inclusions" have a pathogenic role. However, the relationship between inclusion formation and the progressive neurodegeneration in HD remains unclear. Here, we used mice transgenic for the first exon of the HD gene and an expanded CAG repeat (R6/2 line) to examine the role of neuronal intranuclear inclusions in kainic acid (KA) excitotoxicity. Unexpectedly, we found that the toxicity of KA was markedly attenuated in R6/2 mice compared with wild-type mice. In particular, the number and severity of KA-induced seizures in R6/2 mice was significantly reduced. When seizures occurred in 3-week-old R6/2 mice, we found lesions in the CA3 region of the hippocampus. However, neuronal intranuclear inclusions were not induced by KA in 3-week-old mice. Further, in older mice (9 weeks), the pre-existence of inclusions in CA3 neurons did not increase the vulnerability of neurons to KA, since no lesions were seen in 9-week R6/2 mouse brain. Our results suggest that an increased susceptibility to excitotoxic stimuli does not underlie the early phase of the neurological phenotype in R6/2 mice, although a role in later stages is not excluded by our findings. The significance of these findings is discussed in the context of the R6/2 mouse as a model for HD.