Sacral neuromodulation (SNM) has been established as an effective third-line therapy for non-obstructive urinary retention and urinary urgency-frequency syndrome. Device infection, ranging from 2-10%, is a severe complication usually necessitating device explanation. This study sought to demonstrate an infection protocol founded upon established device implantation risk factors and novel approaches to reduce the incidence of device infection, while maintaining good antibiotic stewardship following best practice statements. A single-surgeon protocol was enacted from 2013 to 2022. Preoperatively, nasal swabs were cultured from each patient. If positive for methicillin-resistant Staphylococcus aureus or methicillin-sensitive Staphylococcus aureus, preoperative treatment with intranasal mupirocin was employed. Preoperative cefazolin was administered in patients with negative cultures or MSSA-positive. All protocol patients were given chlorhexidine wipes before surgery and prepped with a chlorhexidine scrub followed by alcohol/iodine paint. Post-procedural antibiotics were not given. Pre-protocol patients from 2011 to 2013 served as controls. Pre-protocol (n=87) patients had a significantly higher rate of device infection compared to protocol patients (n=444) in both the percentage of patients experiencing device infection (4.6% vs 0.9%, p=0.01) and percentage of procedures associated with device infection (2.9% vs 0.5%, p<0.05). A successful culture of the nares was achieved in 91.4% of protocol patients, with 11.6% MRSA-positive. Risk ratio for infection of pre-protocol/protocol patients was 0.19 (0.05-0.77) with odds ratio 5.1 (1.3-20.0). Utilization of a novel SNM infection protocol tailored to a patient's preoperative MRSA colonization is associated with a reduction in the overall incidence of explant for device infection while avoiding prolonged postoperative antibiotic regimens. The study was initiated prior to January 18, 2017 and does not meet the definition of an applicable clinical trial (ACT) as defined in section 402 (J) of the US PHS Act.