Infections are an important complication in the treatment of critical ill patients in Intensive Care Units (ICUs) and are associated with increased mortality, morbidity and health care costs. Selective Decontamination of the Digestive Tract (SDD) and Selective Oropharyngeal Decontamination (SOD) are powerful strategies to reduce the incidence of ICU-acquired infections. SDD consists of a mouth paste and suspension consisting of tobramycin, colistin and amphoterine B that are applied every six hours from ICU-admission until ICU-discharge. In addition, SDD-patients receive systemic antibiotics, usually a third generation cephalosporin, during the first four days in ICU. SOD only consists of the mouth paste. Previous studies have found that both SDD and SOD significantly reduce ICU mortality as compared to no-SDD/SOD use. Controversy still exists which regimen should be preferred and on the effects on antibiotic resistance. In this thesis, the effects of SDD and SOD on patient outcome and antibiotic resistance are studied by conducting a randomized multi-center trial in 16 Dutch ICUs. In this head-to-head comparison between SOD (12months) and SDD (12months) nearly 12,000 patients were included. Regarding their effect on patient outcome, this trial did not show a significant difference between SOD and SDD for mortality (day-28, ICU- and hospital mortality) nor for length of stay. Yet, the incidence of bacteremias was significantly lower during SDD as compared to SOD (p