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Infection is a major cause of death in the intensive care unit (ICU). Strategies to reduce rates of infection in ICUs include selective digestive tract decontamination (SDD), in which cefotaxime and topical antimicrobial agents are administered for 4 days, and selective oropharyngeal decontamination (SOD), in which only topical antimicrobial agents are administered. In this cluster-randomization study involving 13 ICUs in the Netherlands, SOD and SDD did not affect crude mortality but did appear to reduce mortality slightly at day 28, with adjustment for covariates. Strategies to reduce rates of infection in ICUs include selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD). In this study involving 13 ICUs in the Netherlands, SOD and SDD did not affect crude mortality but did appear to reduce mortality slightly at day 28. Infections acquired in the intensive care unit (ICU) are important complications of the treatment of critically ill patients, increasing morbidity, mortality, and health care costs. 1 Reductions in the incidence of respiratory tract infections have been achieved with the use of prophylactic antibiotic regimens, such as selective decontamination of the digestive tract (SDD) 2 , 3 and selective oropharyngeal decontamination (SOD). 4 , 5 The SDD approach 6 , 7 consists of prevention of secondary colonization with gram-negative bacteria, Staphylococcus aureus, and yeasts through application of nonabsorbable antimicrobial agents in the oropharynx and gastrointestinal tract, preemptive treatment of possible infections with commensal respiratory tract bacteria through systemic . . .