Post-operative spine surgical site infections are associated with substantial morbidity, mortality, and economic burden. Intrawound vancomycin may prevent infections after spine surgery, but recent studies have reported conflicting results. The objectives of this systematic review and meta-analysis were to determine: (1) In patients undergoing spine surgery, does the application of intrawound vancomycin lead to reduced rates of post-operative surgical site infections? (2) Are there differences in the estimates of effect between observational studies and randomized trials? (3) What adverse events are reported in the literature?