Emerging antibiotic resistance has become an endemic problem, slowly increasing under the radar and depriving future generations of effective therapies. The goal of REVERSE is to develop and implement cost-effective strategies and tools for the prevention and clinical management of healthcare-associated infections due to multidrug-resistant pathogens, and to reduce the burden of antimicrobial resistance in high prevalence healthcare settings. To achieve these goals, REVERSE will use a mixed-methods approach combining quantitative research with implementation science and economic analysis. The aim is to produce results that go beyond the evidence-base we have today. REVERSE will answer the question about real-life effectiveness of infection prevention and control programmes in combination with antibiotic stewardship on healthcare-associated infections due to multidrug-resistant microorganisms. It will offer implementation strategies to the participating hospitals but also study the effectiveness of external implementation support in a hybrid implementation-effectiveness trial. REVERSE will develop a novel health-economic framework that allows for incorporating of effect of changes in the use of a range of antibiotics on antibiotic resistant infections, and estimating long-term population effects, to integrate both into cost-effectiveness analyses. It will be able to conclude on effectiveness and applicability of prevention strategies in lower-resource settings by cross-checking its programmes with activities in low-and-middle income countries. Four European countries will have a platform of highly experienced hospitals to build on and expand a national network for combatting antibiotic resistance. REVERSE will produce tools and bundles on infection prevention and control, antibiotic stewardship and implementation support. Massive online open courses and other dissemination strategies will make the findings of REVERSE accessible to a wide range of stakeholders.