Severe nosocomial infections and multidrug resistance (MDR) are associated with a poor prognosis for patients in intensive care units. This is partly because most of these patients suffer from high disease severity and acute illness before the onset of infection. Nevertheless, the mortality attributed directly to infection can also be devastating. However, the attributable mortality can be limited by taking account of a number of key points. General infection prevention measures, prevention of cross-transmission and a policy of restricted antimicrobial use are all important because of their positive influence on the rates of infection and MDR. In turn, this will increase the odds for successful empirical coverage of the causative microorganism. Once infection occurs, benefits are to be expected from early recognition of the septic episode and prompt initiation of empirical antimicrobial therapy. The choice of empirical therapy should be based on the local bacterial ecology and patterns of resistance, the presence of risk-factors for MDR, and the colonisation status of the patient. Attention should also be given to adequate doses of antimicrobial agents and, if possible, elimination of the sources of infection, e.g., contaminated devices or intra-abdominal collections or leakages. In the latter case, timely surgical intervention is essential. In addition, haemodynamic stabilisation and optimisation of tissue oxygenation can save lives.