Objective: To determine the influence of microbiologically confirmed infection on hospital mortality among patients requiring intensive care for > 48 h. Design: Prospective cohort study. Setting: Medical ICU of the Barnes-Jewish Hospital, an urban teaching hospital. Patients: A total of 893 patients requiring intensive care for > 48 h. Interventions: Prospective patient surveillance and data collection. Measurements and main results: Three hundred seventy-two patients (41.7%) requiring intensive care for > 48 h had a microbiologically confirmed infection. Only six patients (0.7% [1.6% of patients with microbiologically confirmed infections]) received inadequate antimicrobial therapy during the first 24 h of treatment, and 248 patients (27.8%) died during hospitalization. Compared to hospital survivors, hospital nonsurvivors were significantly more likely to have a microbiologically confirmed infection (53.2% vs 37.2%, respectively; p < 0.001) and to develop severe sepsis (45.6% vs 28.7%, respectively; p < 0.001). Cirrhosis and the requirement for vasopressors were the only variables identified by multiple logistic regression analysis as independent risk factors for hospital mortality in all patient groupings of severity of illness. Multiple logistic regression analysis also demonstrated that underlying malignancy (adjusted odds ratio [AOR], 1.98; 95% CI, 1.55 to 2.53), chronic renal insufficiency (AOR, 1.57; 95% CI, 1.31 to 1.87), cirrhosis (AOR, 1.94; 95% CI, 1.48 to 2.53), temperature > 38.3°C (AOR, 1.72; 95% CI, 1.47 to 2.02), severe sepsis (AOR, 2.78; 95% CI, 1.94 to 3.98), positive culture for vancomycin-resistant enterococci (AOR, 1.78; 95% CI, 1.51 to 2.09), and the presence of multiple infections (AOR, 1.65; 95% CI, 1.28 to 2.14) were independently associated with the requirement for therapy with vasopressors. Conclusions: Microbiologically confirmed infections are common among patients requiring medical intensive care for > 48 h. Despite the administration of adequate antimicrobial therapy, microbiologically confirmed infections appear to be an important cause of hemodynamic instability and increased hospital mortality. These data suggest that clinical efforts aimed at the prevention of infections and improvements in the medical management of patients with severe infections, especially those associated with hemodynamic instability and the need for vasopressors, are required to achieve further improvements in patient outcomes.