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Study Design. A prospective randomized controlled trial. Objective. To assess the ability of local vancomycin powder in controlling postoperative infection in spine surgery. Summary of Background Data. Despite improvements through the use of prophylactic systemic antibiotics, surgical site infections remain a significant problem in spine surgical procedures. Various retrospective and prospective studies have reported the efficacy of local application of vancomycin powder in reducing the infection in animal and human studies. However, there were no randomized control trials that reported on its efficacy. Methods. Prospective randomized controls of 907 patients with various spinal pathologies were treated surgically during a period of 18 months. The control group received standard systemic prophylaxis only, whereas the treatment group received vancomycin powder in the surgical wound in addition to systemic prophylaxis. Patient demographics, comorbidities, level of spinal pathology, estimated blood loss, nutritional status, and hemoglobin were recorded. Incidence of infection was the primary outcome evaluated. Results. There were 8 infections (1.68%) in the control group (6 instrumented and 2 noninstrumented, 6 deep and 2 superficial) with bacteria cultured in 3 (1 Escherichia coil and 2 Staphylococcus aureus). In the treatment group, 7 infections (1.61 %) were observed (6 instrumented and 1 noninstrumented surgical procedures, 6 deep and 1 superficial) with bacteria cultured in 3 (1 Staphylococcus aureus and 2 Klebsiella). No adverse effects were observed from the use of vancomycin powder. Statistically no significant difference was seen in infection rate between the treatment group and control group. Conclusion. The local application of vancomycin powder in surgical wounds did not significantly reduce the incidence of infection in patients with surgically treated spinal pathologies. The use of vancomycin powder may not be effective when incidence of infection is low. [ABSTRACT FROM AUTHOR]