Background: Surgical site infections are not uncommon following spinal operations, and they can be associated with serious morbidity, mortality, and increased resource utilization. The accurate identification of risk factors is essential to develop strategies to prevent these potentially devastating infections. We conducted a case-control study to determine independent risk factors for surgical site infection following orthopaedic spinal operations. Methods: We performed a retrospective case-control study of patients who had had an orthopaedic spinal operation performed at a university-affiliated tertiary-care hospital from 1998 to 2002. Forty-six patients with a superficial, deep, or organ-space surgical site infection were identified and compared with 227 uninfected control patients. Risk factors for surgical site infection were determined with univariate analyses and multivariate logistic regression. Results: The overall rate of spinal surgical site infection during the five years of the study was 2.0% (forty-six of 2316). Univariate analyses showed serum glucose levels, preoperatively and within five days after the operation, to be significantly higher in patients in whom surgical site infection developed than in uninfected control patients. Independent risk factors for surgical site infection that were identified by multivariate analysis were diabetes (odds ratio = 3.5, 95% confidence interval = 1.2, 10.0), suboptimal timing of prophylactic antibiotic therapy (odds ratio = 3.4, 95% confidence interval = 1.5, 7.9), a preoperative serum glucose level of >125 mg/dL (>6.9 mmol/L) or a postoperative serum glucose level of >200 mg/dL (>11.1 mmol/L) (odds ratio = 3.3, 95% confidence interval = 1.4, 7.5), obesity (odds ratio = 2.2, 95% confidence interval = 1.1, 4.7), and two or more surgical residents participating in the operative procedure (odds ratio = 2.2, 95% confidence interval = 1.0, 4.7). A decreased risk of surgical site infection was associated with operations involving the cervical spine (odds ratio = 0.3, 95% confidence interval = 0.1, 0.6). Conclusions: Diabetes was associated with the highest independent risk of spinal surgical site infection, and an elevated preoperative or postoperative serum glucose level was also independently associated with an increased risk of surgical site infection. The role of hyperglycemia as a risk factor for surgical site infection in patients not previously diagnosed with diabetes should be investigated further. Administration of prophylactic antibiotics within one hour before the operation and increasing the antibiotic dosage to adjust for obesity are also important strategies to decrease the risk of surgical site infection after spinal operations. Level of Evidence: Prognostic Level III. See Instructions to Authors for a complete description of levels of evidence.