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Background: This prospective investigation was designed to determine if the postoperative infection rate in instrumented lumbar spinal fusion is affected by postoperative antibiotic use. Methods: Two hundred sixty-nine patients were randomized into either a preoperative only protocol or preoperative with an extended postoperative antibiotic protocol. The preoperative only protocol received a single dose of cefazolin IV. The extended postoperative antibiotic protocol received the same preoperative dose plus postoperative cefazolin IV every 8 hours for 3 days followed by oral cephalexin every 6 hours for 7 days. Because of untoward drug reaction or deviation from the antibiotic protocol, 36 of the 269 patients were eliminated from the study. Therefore, 233 patients completed the entire study. Results: There was no significant difference in infection rates between the 2 antibiotic protocols. The postoperative infection rates were 4.3% for the preoperative only protocol and 1.7% for the preoperative with extended antibiotic protocol. The overall postoperative infection rate was 3%. However, 5 variables of blood transfusion, electrophysiologic monitoring, increased height, increased weight, and increased body mass index appeared to demonstrate a trend toward increase in infection rate. Increased tobacco use trended toward a lower infection rate. Conclusion: Statistical significance was not proven in this prospective study comparing single-dose preoperative antibiotic protocol vs preoperative with an extended postoperative antibiotic protocol. A larger study of 1400 patients would possibly provide more statistically significant information.