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Objective: This proof-of-concept study was conducted to determine whether negative-pressure wound therapy, through the use of incisional vacuum-assisted closure (VAC), is associated with a reduction in surgical site infections (SSIs) when compared to standard wound dressings in patients undergoing open posterior spinal fusion who have a high risk of infection., Methods: A total of 64 patients were examined; 21 patients received incisional VAC application (VAC group) versus 43 diagnosis-matched patients who received standard wound dressings (control group). Patients in the VAC group were prospectively enrolled in a consecutive series between March 2013 and March 2014 if they met the following diagnostic criteria for high risk of infection: posterior open surgery across the cervicothoracic junction; thoracic kyphosis due to metastatic disease; high-energy trauma; or multilevel revision reconstructive surgery. Patients in the VAC group also met one or more comorbidity criteria, including body mass index ≥ 35 or < 18.5, diabetes, previous radiation at surgical site, chemotherapy, steroid use, bedridden state, large traumatic soft-tissue disruption, or immunocompromised state. Consecutive patients in the control group were retrospectively selected from the previous year by the same high-risk infection diagnostic criteria as the VAC group. All surgeries were conducted by the same surgeon at a single site. The primary outcome was SSI. All patients had 1 year of follow-up after their surgery. Baseline demographics, intraoperative parameters, and postoperative wound infection rates were compared between groups., Results: Patient demographics including underlying comorbidities were similar, with the exception that VAC-treated patients were malnourished (p = 0.020). VAC-treated patients underwent longer surgeries (p < 0.001) and required more postoperative ICU admissions (p = 0.039). The median length of hospital stay was not different between groups. In total, 9 control patients (21%) developed an SSI, versus 2 VAC-treated patients (10%)., Conclusions: Patients in this cohort were selected to have an increased risk of infection; accordingly, the rate of SSI was high. However, negative-pressure wound therapy through VAC application to the postoperative incision resulted in a 50% reduction in SSI. No adverse effects were noted secondary to VAC application. The preliminary data confirm the authors' proof of concept and strongly support the need for a prospective randomized trial.