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Background Febrile seizure (FS) is the most common seizure disorders. Approximately one third of children with a febrile seizure have recurrent events. The mechanism of FS remains unclear. Heme oxygenase-1 (HO-1) is a member of the heat shock proteins family and can be induced in the brain by various stresses, including hyperthemia and seizure. This study aimed at investigating the changes of HO-1 in the cortex of rats after recurrent FS.Methods FS in rats was induced ten times, once every 2 days. In a bath of warm water, developing rats were randomly divided into two groups: control group (n=16) and warm water-treated group (n=50). The latter group was subdivided into hyperthermia group (n=19) and FS group (n=23). The expression and content of HO-1 mRNA in cortex were observed using in situ hybridization and quantitative reverse transcription-polymerase chain reaction (RT-PCR). The content of HO-1 protein in cortex was measured using Western blotting. Results HO-1 mRNA expression of cortex neurons in FS group was markedly increased in comparison with those in hyperthermia and control groups (P=0.00), however, there was no statistic difference between hyperthermia group and control group (P=0.16). The relative amount of HO-1 mRNA in cortex in FS group was increased by 53.13% and 96% in comparison with those in hyperthermia group and control group respectively (P=0.00), but there was no obvious difference between the later two groups (P=0.051). Western blotting analysis showed that the HO-1 protein content in cortex in FS group was increased by 198% and 246% in comparison with those in hyperthermia group and control group respectively (P=0.00). There was no obvious difference in HO-1 protein content between the later two groups ( P=0.09).Conclusions Recurrent FS in rats can cause the increase of HO-1 mRNA and protein in cortex which may be involved in the mechanism of FS. The short-time recurrent hyperthermia can not induce the increase of HO-1 mRNA and protein.