© Author(s) (or their employer(s)) 2019. Introduction Care home residents are at increased risk of infections and antibiotic prescription. Reduced antibiotic use from fewer infections would improve quality of life. The Probiotics to Reduce Infections iN CarE home 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 analysis PRINCESS is a double-blind, individually randomised, placebo-controlled trial that will assess the effect of a daily oral probiotic combination of Lactobacillus rhamnosus, GG (LGG) and Bifidobacterium animalis subsp. 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 difficile infection; Gram-negative Enterobacteriaceae and vancomycin-resistant enterococci; LGG and BB-12. Oral microbiology: Candida spp. 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 stimulated ex vivo by toll-like receptor 2 and 4 agonists; monocyte and neutrophil phagocytosis of Escherichia coli; serum vitamin D. Ethics and dissemination Ethics 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 number ISRCTN16392920; Pre-results.