BACKGROUND CONTEXT: Surgical site infections (SSI) are one the most frequent and costly complications following spinal surgery. The SSI rates of different surgical approaches need to be analyzed to successfully minimize SSI occurrence. PURPOSE: The purpose of this study was to define the rate of SSIs in patients undergoing full-endoscopic spine surgery (FESS) and then to compare this rate against a propensity score-matched cohort from the National Surgical Quality Improvement Program (NSQIP) database. DESIGN: This is a retrospective multicenter cohort study using a propensity score-matched analysis of prospectively maintained databases. PATIENT SAMPLE: A total of 1277 noninstrumented FESS cases between 2015 and 2021 were selected for analysis. In the nonendoscopic NSQIP cohort we selected data of 55,882 patients. OUTCOME MEASURES: The occurrence of any SSI was the primary outcome. We also collected any other perioperative complications, demographic data, comorbidities, operative details, history of smoking, and chronic steroid intake. METHODS: All FESS cases from a multi-institutional group that underwent surgery from 2015 to 2021 were identified for analysis. A cohort of cases for comparison was identified from the NSQIP database using Current Procedural Terminology of nonendoscopic cervical, thoracic, and lumbar procedures from 2015 to 2019. Trauma cases as well as arthrodesis procedures, surgeries to treat pathologies affecting more than 4 levels or spine tumors that required surgical treatment were excluded. In addition, nonelective cases, and patients with wounds worse than class 1 were also not included. Patient demographics, comorbidities, and operative details were analyzed for propensity matching. RESULTS: In the nonpropensity-matched dataset, the endoscopic cohort had a significantly higher incidence of medical comorbidities. The SSI rates for nonendoscopic and endoscopic patients were 1.2% and 0.001%, respectively, in the nonpropensity match cohort (p-value <.011). Propensity score matching yielded 5936 nonendoscopic patients with excellent matching (standard mean difference of 0.007). The SSI rate in the matched population was 1.1%, compared to 0.001% in endoscopic patients with an odds ratio 0.063 (95% confidence interval (CI) 0.009-0.461, p=.006) favoring FESS. CONCLUSIONS: FESS compares favorably for risk reduction in SSI following spinal decompression surgeries with similar operative characteristics. As a consequence, FESS may be considered the optimal strategy for minimizing SSI morbidity.