Background:‌ Postoperative infection is a major orthopedic problem that can be reduced by prescribing antibiotics to prevent surgical infection as an effective strategy. Therefore, the present study aimed to evaluate the effectiveness of prophylactic antibiotics to prevent infection in closed lower limb fracture surgery. Methods:‌ The present study was conducted on all patients with closed lower limb fracture from hip to the ankle that underwent Open reduction and internal fixation ‌(ORIF)‌ by a surgeon and received antibiotics and prophylactic antibiotics. The patients who received cefazolin prophylactic antibiotics 1 hour before surgery and 24 hours after surgery were put into the first group. Those receiving cefazolin prophylactic antibiotics 1 hour before surgery and up to 72 hours after surgery were put into the second group. It should be noted that the criterion for the presence of infection was the physician’s clinical judgment based on clinical manifestations such as heat, redness and swelling, pain and infectious secretions, and laboratory tests. Results:‌ Of 140 patients with closed lower limb fractures, two patients‌ (1.4%)‌were infected in each group. The culture of two patients with infection resulted in Staphylococcus aureus, and both patients showed fever and chill symptoms. Infection rates in patients, who received prophylactic antibiotics for 24 hours, had no significant difference with those who received antibiotics for 72 hours ‌(p=0.99).Conclusion:‌ Based on the present study results, the 24-hour prophylactic antibiotic administration to reduce risks of postoperative infection of the closed lower limb fracture in patients can be a suitable alternative for the long-term use of antibiotics.