Background: Surgical site infections (SSIs) represent a devastating complication after spine surgery. Many factors have been identified, but the influence of operating room (OR) size on infection rate has not been assessed. Methods: Two thousand five hundred and twenty-three patients who underwent open lumbar spine fusion at a single institution between 2010 and 2016 were included. Patients were dichotomized into large versus small groups based on OR volume. Bivariate logistic regression and a final multivariate model following a multicollinearity check were used to calculate odds of infection for all variables. Results: A total of 63 patients (2.5%) developed SSIs with 46 (73%) in the larger OR group and 17 (27%) in the smaller OR group. The rate of SSIs in larger ORs was 3.02% compared with 1.81% in smaller ORs. Significant parameters impacting SSI in bivariate analysis included an earlier year of surgery, BMI. 30, more comorbidities, more levels decompressed and fused, smoking, and larger OR volumes. Multivariate analysis identified BMI. 30, Elixhauser scores, smoking, and increasing levels decompressed as significant predictors. Topical vancomycin was found to significantly decrease rate of infection in both analyses. Conclusions: OR size (large versus small) was ultimately not a significant predictor of infection related to rates of SSIs, although it did show a clinical trend toward significance, suggesting association. Future prospective analysis is warranted.