Category: Ankle; Ankle Arthritis; Arthroscopy; Bunion; Hindfoot; Midfoot/Forefoot; Sports; Trauma Introduction/Purpose: The use of intraoperative topical vancomycin powder has recently increased in popularity as a method of theoretically decreasing post-operative surgical site infections; however, there is limited research in orthopaedic trauma to support its use. This study evaluates the use of topical vancomycin powder to decrease post-operative infections following lower extremity trauma. We also investigated socio-demographic factors and medical comorbidities that were associated with post- operative surgical site infections. Methods: We conducted a review of 226 patients at a single Level 1 Trauma Center following surgery between the years 2015 and 2020. These patients were treated predominantly by a single fellowship trained foot and ankle orthopaedic surgeon. Demographic factors, medical comorbidities, postoperative infections, and use of vancomycin powder were reviewed. Analysis of 4 groups (no infection, superficial infection, deep infection, or both) was performed using Fischer's exact test and Student t-test. A logistic regression model was utilized to identify independent demographic factors and medical comorbidities that were associated with surgical site infection. Results: The final cohort included 221 patients, of which 26 received intraoperative vancomycin powder. There were 23 total post-operative surgical site infections. Of those, 14 infections were superficial, 3 were deep, and 6 were both superficial and deep. All but one of these infections were in patients without vancomycin powder applied. Patients who received intraoperative vancomycin powder were statistically significantly less likely to acquire post-operative surgical site infections than those who did not (1 vs. 22, p=0.031). The one postsurgical site infection with vancomycin use was a deep infection in a patient with chronic kidney disease that had previously undergone three irrigation and debridement surgeries for a gunshot wound. Male sex was the only demographic or comorbidity factor associated with postoperative surgical site infection (p=0.009, OR=4.006). Conclusion: We found an association between topical vancomycin use and lower likelihood of developing postsurgical wound infections in lower extremity trauma. This is consistent with similar studies in spinal surgery. In contrast to previous studies, we did not find a significant association between medical comorbidities or demographic factors other than male sex and surgical site infection. Future studies should aim to identify which patients would have the greatest reduction of risk for postsurgical wound infections with the use of intraoperative topical vancomycin powder.