BACKGROUND AND OBJECTIVES: Surgical site infections (SSI) in neurosurgery result in prolonged hospitalizations, readmissions, poor outcomes, and even death. Prevention of SSI remains paramount to mitigate the risk of this complication. In this study, we aimed to evaluate the effect of topical use of vancomycin powder during surgical closure in cranial surgery for the reduction of SSI. METHODS: This is a retrospective cohort study of cranial neurosurgical patients from 2016 to 2022 in Fundación Santa Fe de Bogotá. Baseline clinical and surgical characteristics were collected, as well as vancomycin powder use. The primary outcome of interest was SSI within 90 days after surgery. A P value of .05 was considered significant. RESULTS: We found a total of 1395 patients, of which 1108 met the selection criteria. Surgical site infection was seen in 32 patients (2.9%). Topical use of vancomycin powder during surgical closure was associated with a lower frequency of SSI in cranial surgery n = 10 (2.3%) relative to those who did not use vancomycin n = 22 (3.3%), and it was found to be a protective factor in the multinomial regression, with a statistically significant result (relative risk = 0.397, P = .034). CONCLUSION: The evidence supporting the use of vancomycin powder during surgical closure is currently weak, as the association did not reach statistical significance in the primary analysis. However, a P value of less than 0.05 was obtained in the multivariate analysis. To further assess the efficacy of this intervention, additional randomized prospective studies are needed.