Purpose::The role of topical vancomycin in fracture-related infection (FRI) is debatable. Very few studies have reported their efficacy in open and high-risk extremity fractures. This study aimed to assess topical vancomycin's role in reducing FRI in closed fractures undergoing open surgical intervention with an implant.Methods::This prospective randomized cohort study was carried out between February 2021 to January 2022. Patients with isolated closed fractures, who were planned for open reduction and internal fixation within 2 weeks from the time of injury were included for this study. The data collected included age, gender, socioeconomic status, mechanism of injury, diagnosis, Tscherne classification, and time interval to take up for surgery. Patients were randomized into the intervention and control groups using the block randomization technique. The control group received only systemic antibiotic prophylaxis, whereas the intervention group received topical application of vancomycin powder in the surgical wound alongside systemic antibiotic prophylaxis. The primary outcome measure was the incidence of FRI among these individuals. Clinical and radiological findings and culture reports (in cases with infection) were recorded during the post-operative period and at 6 weeks of follow-up. All relevant statistical calculations were done using STATA statistical/data analysis-parallel edition version 16.0 (StataCorp LLC). The quantitative variables like age and duration of the surgery were assessed for normalcy by Shapiro-Wilk W test. An independent samples t-test with equal variances was applied to the age data. Fisher's exact test was used for the analysis of the primary outcome measure (presence of FRI following surgery), and "Risk of FRI" and "Risk difference" between the 2 groups was calculated. The strength of the association between qualitative variables was assessed using the Fisher's exact and Chi-square tests, respectively. Results::There were 88 patients included in this study. No statistical significance was found about FRI between both groups ( p = 0.494). At 6 weeks following surgery, no incidence of infection was observed in the intervention group. Two infections (4.5%) were found in the control group, with positive cultures reported in one of them but none in the treatment group. Radiologically, 15.9% of patients in the control group showed lysis around the implant compared to 2.3% in the intervention group. Impaired fracture healing was observed in 22.7% of patients in the intervention group compared to 15.9% in the control group. Conclusion::Applying topical vancomycin in closed fractures undergoing open reduction and internal fixation does not significantly reduce the incidence of FRI until the end of 6 weeks following surgery.