Study Design:Retrospective cohort study.Objective:The authors’ goal was to clarify whether a bone substitute combined with antibiotics might gain a hold in spinal surgery as a preventive treatment for early infections (EIs).Background:A relatively infrequent but severe complication in spinal surgery is the occurrence of EIs.Methods:The authors retrospectively compared a population undergoing posterolateral fusion with Mg-enriched hydroxyapatite paste mixed with 60 mg rifampicin powder, with a matched population treated with autologous bone without antibiotics. A total of 30 patients from 2020 to 2021 were included in our study. We estimated EI’s relative risk and the number needed to treat. Statistical analyses were performed using the R statistical package v3.4.1 (http://www.r-project.org).Results:No early infections occurred in the population treated with antibiotic-combined bone substitutes, compared with 6.7% of patients treated with autologous bone without antibiotics. The relative risk of EIs was 0.33 (P=.49; 95% CI=0.01–7.58) and the number needed to treat was 15.Conclusions:The results support the hypothesis that combining bone substitutes with antibiotics may decrease the risk of EIs and could be a viable option to improve spinal surgery outcomes. However, a larger sample size would be needed to confirm the benefit of rifampicin-combined Mg-enriched hydroxyapatite substitutes over autologous bone for surgical site infection prevention.Level of Evidence:Level 3.