ScopeThe aim of these guidelines is to provide recommendations on decolonization and perioperative antibiotic prophylaxis (PAP) in multidrug-resistant Gram-positive bacteria (MDR-GPB) adult carriers before inpatient surgery. MethodsThese European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/European Committee on Infection Control (EUCIC) guidelines were developed following the systematic review of published studies targeting methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), methicillin-resistant coagulase-negative staphylococci (MR-CoNS) and pan-drug-resistant (PDR)-GPB. Critical outcomes were the occurrence of surgical site infections (SSIs) caused by the colonizing MDR-GPB and SSIs-attributable mortality. Important outcomes included the occurrence of SSIs caused by any pathogen, hospital-acquired infections, all-cause mortality, and adverse events associated with the interventions, including resistance development to the agents used and incidence of Clostridioides difficile infections. The last search of all databases was performed on November 1st, 2023. The level of evidence and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached for the final list of recommendations. Antimicrobial stewardship considerations were included. RecommendationsThe guideline panel reviewed the impact of decolonization, targeted PAP, and combined interventions (e.g., decolonization and targeted PAP) on the risk of SSIs and other outcomes in MDR-GPB carriers, according to the type of bacteria and type of surgery.We recommend screening for S. aureus (SA) before high-risk operations, such as cardiothoracic and orthopedic surgery. Decolonization with intranasal mupirocin with or without chlorhexidine bathing is recommended in patients colonized with SA before cardiothoracic and orthopedic surgery and suggested in other surgeries. Addition of vancomycin to standard prophylaxis is suggested for MRSA carriers in cardiothoracic surgery, orthopedic surgery, and neurosurgery. Combined interventions (e.g., decolonization and targeted prophylaxis) are suggested in MRSA carriers undergoing cardiothoracic and orthopedic surgery. No recommendation could be made regarding screening, decolonization, and targeted prophylaxis for VRE due to the lack of data. No evidence was retrieved for MR-CoNS and PDR-GPB. Careful consideration of the laboratory workload and involvement of antimicrobial stewardship as well as infection control teams are warranted before implementing screening procedures or performing changes in PAP policy. Future research should focus on novel decolonizing techniques, on the monitoring of resistance to decolonizing agents and PAP regimens, and on standardized combined interventions in high-quality studies.