BackgroundAntimicrobial prophylaxis (AMP) is one of the most important measures for preventing surgical site infections (SSIs); however, controversies remain regarding its adequate duration. Although the World Health Organization and the Center for Disease Control and Prevention do not recommend additional AMP after closure, the American Society of Health-System Pharmacists and the Musculoskeletal Infection Society permit the use of postoperative AMP, but recommend discontinuation within 24 h. Similarly, the Japanese Society of Chemotherapy and the Japan Society for Surgical Infection also permit AMP within 24–48 h after various orthopaedic procedures. In these guidelines, recommendations regarding AMP duration were weak due to a relative lack of evidence, and currently, there is no high-quality evidence comparing AMP use within 24 h versus 24–48 h regarding orthopaedic procedures. Urinary tract infection (UTI) and respiratory tract infection (RTI) are also important health care-associated infections (HAIs) faced after surgery. Although AMP duration may affect these HAIs, its effects have not been well evaluated.MethodsWe have organized a multicenter, prospective, cluster pseudo-randomized controlled trial to examine the non-inferiority of shorter AMP duration (within 24 h) against longer duration (24–48 h) in preventing postoperative HAIs. Participating facilities will be divided into two groups. In Group 24, AMP will be discontinued within 24 h after surgery. In Group 48, AMP will be discontinued within 24–48 h after surgery. The group allocation will be switched every 2 months until the targeted recruitment (500 participants per group) is met.The primary outcome will be the cumulative incidence of all HAIs (SSI, UTI, RTI, and other infectious diseases), which require antibiotic therapies within 30 days after surgery. In addition to mortality and cardiovascular events, prolonged hospitalization (> 30 days) and the rate of antibiotic resistance rate of SSI pathogens will also be evaluated. Outcomes will be evaluated within 30–180 days after surgery in person by the surgeon, by mail, or by telephone survey. Data will be analyzed by a statistician not engaged in data collection.DiscussionThis study may provide valuable information for developing future recommendations for adequate AMP duration after clean orthopaedic surgery.Trial registrationUMIN000030929, registered January 22, 2018.