To retrospectively analyze if the use of topical intraoperative vancomycin powder reduces deep surgical site infection (DSSI) after posterior lumbar interbody fusion.All spinal surgeries for lumbar degenerative disease and underwent posterior fixation interbody fusion between January 2013 and December 2018 were reviewed. A total of 891 patients were included, of which 527 patients (treatment group) received intraoperatively topical vancomycin powder; the others were served as control group. The primary outcomes were the overall incidence of DSSI and the effect of vancomycin on its development. The secondary outcome was risk factors for DSSI. Data on the baseline characteristics, postoperative complications, perioperative risk factors, and one-year postoperative prognoses were extracted from the medical records.A total of 20 patients met the diagnostic criteria for DSSI (2.24%), of which 7 patients (1.33%) in the treatment group and 13 patients (3.57%) in the control group. There was a significant difference in the incidence of DSSI between the groups (P = 0.026). Multivariate logistic regression analysis with stepwise backward elimination showed that the local use of vancomycin powder was an independent protective factor for DSSI (odds ratio (OR): 0.25, P = 0.01), whereas high body mass index (BMI) (OR: 1.21, P = 0.005), drinking (OR: 5.19, P = 0.005), urinary tract infections (OR: 4.49, P = 0.021), diabetes mellitus (OR: 4.32, P = 0.03), and blood transfusions (OR: 3.67, P = 0.03) were independent risk factors for DSSI.The intraoperative usage of vancomycin powder could reduce effectively decreases the incidence of DSSI after posterior lumbar interbody fusion for degenerative lumbar diseases. High BMI, diabetes mellitus, drinking, and urinary tract infections were independent risk factors for DSSI, whereas the local use of vancomycin protected against these factors.© 2022 Wang et al.