Background: Clean surgical procedures such as hip and knee replacement and spine surgery have a low infection complication rate; however, if infections occur, there is substantial morbidity and increased cost. Staphylococcus aureus causes 30% of surgical site infections (SSIs). S. aureus colonization increases the risk of developing SSI. Nasal povidone-iodine 5% application reduces the S. aureus colonization burden. Objective: We aimed to reduce SSIs by applying nasal povidone-iodine 5% prior to hip and knee replacement and spine surgery. Methods: Adult patients hospitalized for elective hip replacement, knee replacement, or spine surgeries from February 2018 through August 2019 comprised the study cohort. All patients received preoperative guidance in the outpatient clinic. On admission, the evening before surgery, a nasal swab for S. aureus colonization was performed, followed by povidone-iodine 5% application in both nostrils and body chlorhexidine gluconate 4% bathing. Application of these substances was repeated in the morning before surgery. Within 24 hours after surgery, an additional nasal swab for S. aureus colonization was taken. A 90-day follow-up for SSI was done. Data were compared with a similar 2016–2017 cohort without the preoperative measures. Results: In total, 186 patients were included: 85 underwent hip or knee replacement (age 69 ± 13.2 y, 66% men), and 101 spine surgery (age 55 ± 15.4 y, 52% men). At screening, 18.3% were colonized with methicillin-sensitive S. aureus and 1.6% colonized with methicillin-resistant S. aureus. Pre- and postsurgery data for the cohort appear in Table 1. The SSI rate per 100 patient days for hip and knee replacement and for spine surgery decreased from 0.29 and 4.0, respectively, in the 2016–2017 cohort to 0 and 0.99, respectively, in the present cohort. Conclusions: Nasal povidone-iodine 5% reduced the S. aureus colonization burden. The SSI rate in elective hip and knee replacement and spine surgery significantly decreased. We show that there is no need for S. aureus eradication presurgery; semiquantitative S. aureus nasal colony reduction should suffice in reducing SSIs. Further research is needed using quantitative measurements for S. aureus colonization.