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STUDY DESIGN Retrospective cohort study. OBJECTIVE The aim of the current investigation was to evaluate the impact of prolonged prophylactic systemic antibiotics (PPSA) on the development of surgical site infection rate (SSIR) in degenerative spine surgery. SUMMARY OF BACKGROUND DATA Surgical drains are utilized postoperatively in posterior spine surgery to help minimize the risk of seroma formation. Prophylactic antibiotics while drains are in place are frequently used to reduce SSIR, though the practice remains controversial. METHODS We performed a single center, retrospective review of all patients that underwent posterior spinal surgery for cervical and lumbar degenerative pathology over a 3.5 year period (January 2016-July 2019). Patients underwent a traditional open posterior midline procedure with postoperative placement of a subfascial surgical drain. Antibiotics were administered for the duration of the drain (PPSA group) or for 24 hours postoperatively (non-PPSA group). The number of surgical site infections, organism, and Clostridium difficile infections was recorded. RESULTS Three hundred thirty six patients were identified, 168 patients in the PPSA group and 168 in the non-PPSA groups. The overall SSIR was 5.36% (18/336). The SSIR for the non-PPSA and PPSA groups were 7.14% (12/168) and 3.57% (6/168), respectively (P = 0.146). While difference of SSIR between the groups was two-fold, it was not statistically significant. For the non-PPSA and PPSA groups, the SSIR for cervical (5.95% [5/84] vs. 2.38% [2/84], P = 0.443) and lumbar (8.33% [7/84], vs. 4.76% [4/84], P = 0.535) regions were not significantly different. C. difficile cases in the PPSA and non-PPSA groups were 1/168 and 0/168 respectively (P = 1.00). CONCLUSION Our series demonstrate a two-fold reduction of SSI with implementation of PPSA regimen. This benefit was demonstrated separately for both cervical and lumbar regions. Randomized trials and increase in sample size are warranted to elucidate the significance of PPSA in posterior spinal surgery.Level of Evidence: 3.