The relationship between heat shock protein 72 (HSP72) and c-fos gene expression following systemic administration of kainic acid was investigated by combining immunocytochemistry for HSP72 with in situ hybridization for c-fos. Increased HSP72 expression was detected in adult rat hippocampus 4 h after seizure-onset. Transient co-expression of c-fos and HSP72 occurred in neurons that are resistant to kainic acid, whereas prolonged co-expression was observed in vulnerable neurons. The spatial distribution and developmental time course of kainic acid-induced HSP72 expression were similar to those of kainic acid-induced neurodegeneration. The results demonstrate a relationship between c-fos and HSP72 gene expression and suggest that prolonged co-expression of these genes plays a role in kainic acid-induced neuronal death.