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OBJECTIVE To reduce transmission of carbapenem-resistant Enterobacteriaceae (CRE) in an intensive care unit with interventions based on simulations by a developed mathematical model. DESIGN Before-after trial with a 44-week baseline period and 24-week intervention period. SETTING Medical intensive care unit of a tertiary care teaching hospital. PARTICIPANTS All patients admitted to the unit. METHODS We developed a model of transmission of CRE in an intensive care unit and measured all necessary parameters for the model input. Goals of compliance with hand hygiene and with isolation precautions were established on the basis of the simulations and an intervention was focused on reaching those metrics as goals. Weekly auditing and giving feedback were conducted. RESULTS The goals for compliance with hand hygiene and contact precautions were reached on the third week of the intervention period. During the baseline period, the calculated R0 was 11; the median prevalence of patients colonized by CRE in the unit was 33%, and 3 times it exceeded 50%. In the intervention period, the median prevalence of colonized CRE patients went to 21%, with a median weekly Rn of 0.42 (range, 0-2.1). CONCLUSIONS The simulations helped establish and achieve specific goals to control the high prevalence rates of CRE and reduce CRE transmission within the unit. The model was able to predict the observed outcomes. To our knowledge, this is the first study in infection control to measure most variables of a model in real life and to apply the model as a decision support tool for intervention. Infect Control Hosp Epidemiol 2016;1-8.