Background The preoperative body surface and nasal decolonization may reduce the risk of surgical site infections (SSI), but yields conflicting results in the current orthopedic literature. Methods We perform a single-center, randomized-controlled, superiority trial in favor of the preoperative decolonization using a commercial product (octenidin® set). We will randomize a total number of 1,000 adult elective orthopedic patients with a high risk for SSI and/or wound complications (age ≥ 80 years, chronic immune-suppression, American Society of Anesthesiologists’-Score 3–4 points) between a decolonization (octenisan® wash lotion 1 x per day and octenisan® md nasal gel 2–3 x per day; during five days) and no decolonization. Decolonized patients will additionally fill a questionnaire regarding the practical difficulties, the completeness, and the adverse events of decolonization. The primary outcomes are SSI and revision surgeries for postoperative wound problems until six weeks postoperatively (or 1 year for surgeries with implants or bone). Secondary outcomes are unplanned revision surgeries for non-infectious problems and all adverse events. With 95% event-free surgeries in the decolonization arm versus 90% in the control arm, we formally need 2 x 474 elective orthopedic surgeries included during two years. Discussion In selected adult orthopedic patients with a high risk for SSI, the presurgical decolonization may reduce postoperative wound problems, including SSI. Trial registration ClinicalTrial.gov NCT05647252. Registered on 9 December 2022. Protocol version 2 (5 December 2022)