Background: Post-surgical invasive Staphylococcus aureus infections among spinal fusion patients are serious complications that can worsen clinical outcomes and increase healthcare utilization. Risk of such infections at the population level remains unknown. This study assessed the post-surgical risk of invasive Staphylococcus aureus infections among patients undergoing elective posterior instrumented spinal fusion surgeries in 129 U.S. hospitals. Patients and Methods: This retrospective cohort study analyzed adult patients ≥18 years of age who underwent thoracolumbar/lumbar and cervical fusion surgeries during 2010 – 2014 using the Premier Healthcare Database, the largest hospital discharge database in the United States. Risks of blood stream infection (BSI), deep or organ/space surgical site infections (SSI) caused by Staphylococcus aureus during 90 and 180 days post-index surgery were estimated. Infections were identified based on positive culture results, related International Classification of Diseases, Ninth Revision (ICD-9) procedure codes, and specific claims information. Results: Among 11,236 patients with thoracolumbar/lumbar fusion, 90- and 180-day BSI/SSI infection risks were higher for multilevel than single level fusion (90-day, 1.52% vs. 1.07%, p = 0.05; 180-day, 1.66% vs. 1.07%, p = 0.014). Among 1,641 patients with cervical fusion, 90- and 180-day BSI/SSI infection risks were also higher in multilevel fusions but not statistically significant (90-day, 1.66% vs. 0.52%, p = 0.350; 180-day, 1.80% vs. 0.51%, p = 0.241). The risk for SSI/BSI was more than twice as high among multilevel thoracolumbar/lumbar fusion patients with more than two comorbidities than those with no comorbidity at both 90-day (2.78% vs. 1.00%, p < 0.05) and 180-day (3.01% vs. 1.10%, p < 0.05). Similar trend without statistical significance was seen in multilevel cervical fusion cohort (90-day, 2.91% vs. 1.25%, p > 0.05; 180-day, 3.88% vs. 1.41%, p > 0.05). Conclusions: The risk of BSI/SSI infection for elective posterior instrumented spinal fusions ranged between 0.5% and 2%. Higher risk was observed in multilevel thoracolumbar/lumbar surgery, with infection risk greatest in patients with more than two comorbidities. These real-world findings highlight the need for additional measures, in addition to antibiotic prophylaxis, to reduce invasive Staphylococcus aureus infections in this setting.