Objective: Febrile seizure (FS) is the most common form of childhood seizure disorder, it is perhaps one of the most frequent causes of admittance to pediatric emergency wards worldwide. We aimed to identify a new, safe, and effective therapy for preventing FS recurrence. Methods: A total of 115 children with a history of two or more episodes of FS were randomly assigned to the levetiracetam (LEV) and control (LEV: control ratio 2:1) groups. At the onset of febrile, the LEV group was orally administered with a dose of 15 mg/kg/d to 30 mg/kg/d twice daily for 1 week and then dosage was gradually reduced until totally removed in the 2nd week. The primary efficacy variable was seizure frequency associated with febrile events and FS recurrence rate during 48-week follow-up, the second outcome was the cost-effectiveness of two groups. Results: The intention-to-treat analysis showed that 11 children experienced 148 febrile episodes and 15 FS recurrences in the LEV group and 19 children experienced 64 febrile episodes and 32 FS recurrences in the control group. There was significant difference between two groups in FS recurrence rate and FS recurrence/fever episode. The cost of LEV for prevention of FS recurrence is much lower than that of control group. During the 48-week follow up period, one patient in the LEV group exhibited severe drowsiness, no other side effects were observed in the same patient and in other children. Conclusion: Intermittent oral LEV can effectively prevent FS recurrence, and reduce waste of medical resources.