In a control group of 59 multiple trauma patients requiring prolonged intensive care, a conventional restrictive antibiotic policy was followed. Forty-eight patients (81%) developed 94 infections. Fifty-one patients received systemic antibiotic therapy with one or more drugs. The total quantity of systemic antibiotics used was very high (18.3±22.1 antibiotic days per patient). This policy resulted in a very high incidence of superinfections (24%) with multiply-resistant Gram-negative bacteria, mostly emerging from the digestive tract (secondary endogenous infections). Five patients died from infection. A novel technique of infection prevention, based on the maintenance of the colonization resistance and on selective decontamination of the digestive tract in combination with systematic antibiotic prophylaxis with cefotaxime, proved to be very effective. Out of 63 multiple trauma patients, intubated and ventilated for 5 days or more in the ICU, 10(16%) developed 11 infections. Most infections occurring under this regimen were primary endogenous infections which were treated by continuation of cefotaxime. Only two patients (3%) developed a superinfection with cefotaximeresistant Gram-negative bacteria. No patient died. This approach to infection prevention in the ICU, shows that prophylactic administration of antibiotics significantly reduced the infection rate of critically ill patients without the development of superinfection.