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Surgical site infection after spine surgery is a well-known complication that can result in poor outcomes, arthrodesis-site nonunion, and neurological injury. We hypothesized that a higher surgical invasiveness score will increase the risk for surgical site infection following spine surgery.Data were examined from patients undergoing any type of spinal surgery from January 1, 2003, to December 31, 2004, at two academic hospitals. The surgical invasiveness index is a previously validated instrument that accounts for the number of vertebral levels decompressed, arthrodesed, or instrumented as well as the surgical approach. Relative risks and 95% confidence intervals were calculated for each of the categorical variables. Multivariate binomial stepwise logistic regression was used to examine the association between surgical invasiveness and surgical site infection requiring a return to the operating room for treatment, adjusting for confounding risk factors.The regression analysis of 1532 patients who were evaluated for surgical site infection identified the following significant risk factors for surgical site infection: a body mass index of >35 (relative risk, 2.24 [95% confidence interval, 1.21 to 3.86]; p = 0.01), hypertension (relative risk, 1.73 [95% confidence interval, 1.05 to 2.85]; p = 0.03), thoracic surgery versus cervical surgery (relative risk, 2.57 [95% confidence interval, 1.20 to 5.60]; p = 0.01), lumbosacral surgery versus cervical surgery (relative risk, 2.03 [95% confidence interval, 1.10 to 4.05]; p = 0.02), and a surgical invasiveness index of >21 (relative risk, 3.15 [95% confidence interval, 1.37 to 6.99]; p = 0.01).Patients undergoing more invasive spine surgery as measured with the surgical invasiveness index had greater risk for having a surgical site infection that required a return to the operating room for treatment. Surgical invasiveness was the strongest risk factor for surgical site infection, even after adjusting for medical comorbidities, age, and other known risk factors. The magnitude of this association should be considered during surgical decision-making and intraoperative and postoperative care of the patient. These findings further validate the importance of the invasiveness index when performing safety and clinical outcome comparisons for spine surgery.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.