This study investigates the contribution of the patient microbiome to surgical site infections (SSIs) and antibiotic prophylaxis failure in spine surgery. Using a prospective cohort of 204 patients, the researchers collected preoperative microbiome samples and postoperative SSI isolates. They found that 86% of SSIs originated from preoperative strains, with no evidence of common-source infection among a larger cohort of 1,610 patients. Most SSI isolates (59%) were resistant to the prophylactic antibiotic used during surgery, and their resistance phenotypes correlated with the patient's preoperative resistome. The study highlights the need for SSI prevention strategies tailored to the individual patient's preoperative microbiome and resistome. The findings suggest that endogenous routes of infection, rather than exogenous sources, are primarily responsible for SSIs in spine surgery.This study investigates the contribution of the patient microbiome to surgical site infections (SSIs) and antibiotic prophylaxis failure in spine surgery. Using a prospective cohort of 204 patients, the researchers collected preoperative microbiome samples and postoperative SSI isolates. They found that 86% of SSIs originated from preoperative strains, with no evidence of common-source infection among a larger cohort of 1,610 patients. Most SSI isolates (59%) were resistant to the prophylactic antibiotic used during surgery, and their resistance phenotypes correlated with the patient's preoperative resistome. The study highlights the need for SSI prevention strategies tailored to the individual patient's preoperative microbiome and resistome. The findings suggest that endogenous routes of infection, rather than exogenous sources, are primarily responsible for SSIs in spine surgery.