Objective To investigate the effect of amiloride on complex febrile seizures and the possible mechanism.Methods Young Sprague-Dawley (SD) rats were used to establish a model of complex febrile seizures. A total of 40 young SD rats were divided into normal control group, febrile seizure group, amiloride pretreatment groups (at doses of 1.3 and 10 mg/kg, respectively), with 10 rats in each group. The effect of amiloride pretreatment on the increase in body temperature and latency period of seizures was observed during febrile seizures, as well as its effect on the number of astrocytes and the mRNA expression of interleukin-1β (IL-1β) in the hippocampus.Results In the febrile seizure group, the body temperature reached 39.5℃ in 4.3-6.8 minutes, and in the 1.3 and 10 mg/kg amiloride pretreatment groups, the body temperature reached 39.5℃ in 8.3-10 and 9.3-11.6 minutes, respectively, suggesting that the latter two groups had a significantly longer time for body temperature to reach 39.5℃ than the former group (P<0.01); there was also a significant difference between the 1.3 and 10 mg/kg amiloride pretreatment groups (P<0.05). The 1.3 mg/kg amiloride pretreatment group had a latency period of seizures of 10.67-14.50 minutes and a threshold of body temperature of 41.3-42.1℃, and the 10 mg/kg amiloride pretreatment group had a latency period of seizures of 12.33-16.60 minutes and a threshold of body temperature of 41.4-42.1℃; the febrile seizure group had a latency period of seizures of 7.67-9.50 minutes and a threshold of body temperature of 41.0-41.7℃. Compared with the febrile seizure group, the 1.3 and 10 mg/kg amiloride pretreatment groups had a significant increase in the latency period of seizures and a significantly higher threshold of body temperature (P<0.01); there were also significant differences in the latency period of seizures and threshold of body temperature between the two amiloride pretreatment groups (P<0.05). The amiloride pretreatment groups had a significant increase in the number of astrocytes compared with the normal control group and a significant reduction compared with the febrile seizure group (both P<0.01). The amiloride pretreatment groups had significantly lower mRNA expression of IL-1β than the febrile seizure group (P<0.01).Conclusions Amiloride can prevent complex febrile seizures, possibly by inhibiting the proliferation of astrocytes and the production of inflammatory cytokines.