IntroductionDecontamination regimen decreases acquired infection (ICU-AI) incidence but has remained controversial, mostly because it contains a course of intravenous antibiotic. Multiple-site decontamination (MSD), which does not include systemic antibiotics, has been less widely studied but is associated with lower risks of ventilator-associated pneumonia (VAP), bloodstream infection (BSI) and multidrug resistant micro-organism (MDRO) acquisition. We aimed to confirm these favorable outcomes. MethodsA prospective pre/post-observational study was conducted in 5 ICUs in western France. Among them, 4 implemented MSD, whereas the fifth applied standard care (SC) throughout the study period. Patients who required intubation were eligible for study and divided into two groups: the MSD group if they were admitted to an ICU that already implemented MSD, or the SC group. The primary objective was to measure ICU-AI incidence. ResultsClose to 1400 (1346) patients were available for analysis (334 in the MSD and 1012 patients in the SC group). In a multivariable Poisson regression model, MSD was independently associated with decreased incidence of ICU-AI (IRR = 0.33; 95 %CI [0.18–0.60] p < 0.001). Non-parsimonious propensity-score matching resulted in 334 patient-pairs with well-balanced baseline characteristics. There was a lower incidence of ICU-AI(6.3 % vs 20.7 % p < 0.001), VAP (3.6 % vs 16.2 % p < 0.001) and BSI (3.0 % vs 7.2 % p = 0.029) in the MSD group as compared with the SC group. Five (1.5 %) and 11 (3.3 %) patients respectively acquired MDRO (p = 0.206). ConclusionMSD is associated with decreased risk of ICU-AI, VAP and BSI, with no increase in MDRO acquisition.