OBJECTIVE: Febrile seizure (FS) is the most common type of seizure disorders in children. Recurrent FS can cause hippocampal neurons injury. At the same time heme oxygenase/ carbon monoxide (HO/CO) system and nitric oxide sythase/ nitric oxide (NOS/NO) system were up-regulated and interacted each other. This study examined the effects of the two systems on the apoptosis of hippocampal neurons in rats with recurrent FS. METHODS: FS was induced in rats by exposure to warm water bath (45.2 ℃), once every 2 days, 10 times in all. Sprague-Dawley (SD) rats aged 21 days were randomly assigned into four groups: Control (37 ℃ water bath exposure), FS, FS + ZnPP-Ⅸ (HO inhibitor) and FS+ L-NAME (NOS inhibitor) groups. The apoptosis of hippocampal CA1 neurons was detected by TUNEL. RESULTS: After recurrent FS, the apoptotic cells in the hippocampal CA1 neurons increased by 225% compared with those in the Control group (P<0.01). The apoptotic cells in the FS+ZnPP-Ⅸ group increased by 62% and 425% compared with those in the FS and the Control groups (both P <0.01). The apoptotic cells in the FS+L-NAME group decreased by 38% compared with those in the FS group (P<0.01) and increased by 100% compared with those in the Control group ( P<0.05 ). CONCLUSIONS: onclusions In recurrent FS, exogenous administration of HO inhibitor ZnPP-Ⅸ may induce an increase of apoptotic cells in hippocampal neurons, while NOS inhibitor L-NAME may decrease the apoptotic cells. The results suggest that the HO/CO system might alleviate neuronal damage, while NOS/NO system might augment neuronal damage.