IntroductionCare home residents are at increased risk of infections and antibiotic prescription. Reduced antibiotic use from fewer infections would improve quality of life. TheProbiotics toReduceInfections iN CarEhome reSidentS(PRINCESS) trial aims to determine the efficacy and investigate mechanisms of daily probiotics on antibiotic use and incidence of infections in care home residents.Methods and analysisPRINCESS is a double-blind, individually randomised, placebo-controlled trial that will assess the effect of a daily oral probiotic combination ofLactobacillus rhamnosus,GG (LGG) andBifidobacterium animalissubsp.lactis, BB-12 (BB-12) on cumulative antibiotic administration days (CAADs) (primary outcome) for infection in up to 330 care home residents aged ≥65 years over up to 12 months. Secondary outcomes include:Infection:Total number of days of antibiotic administration for each infection type (respiratory tract infection, urinary tract infection, gastrointestinal infection, unexplained fever and other); number, site, duration of infection; estimation of incidence and duration of diarrhoea and antibiotic-associated diarrhoea;Stool microbiology:Clostridium difficileinfection; Gram-negative Enterobacteriaceae and vancomycin-resistant enterococci; LGG and BB-12.Oral microbiology: Candidaspp.Health and well-being:Self and/or proxy health-related quality of life EQ5D (5 L); self-and/or proxy-reported ICEpop CAPability measure for older people.Hospitalisations:number and duration of all-cause hospital stays.Mortality:deaths.Mechanistic immunology outcomes:influenza vaccine efficacy (haemagglutination inhibition assay and antibody titres); full blood count and immune cell phenotypes, plasma cytokines and chemokines; cytokine and chemokine response in whole blood stimulatedex vivoby toll-like receptor 2 and 4 agonists; monocyte and neutrophil phagocytosis ofEscherichia coli; serum vitamin D.Ethics and disseminationEthics approval is from the Wales Research Ethics Committee 3. Findings will be disseminated through peer-reviewed journals and conferences; results will be of interest to patient and policy stakeholders.Trial registration numberISRCTN16392920; Pre-results.