Intensive-care-unit (ICU) patients are at risk for both acquiring nosocomial infection and dying, and require a high level of therapy whether infection occurs or not. The objective of the present study was to precisely define the interrelationships between underlying disease, severity of illness, therapeutic activity, and nosocomial infections in ICU patients, and their respective influences on these patients' outcome. In a 10-bed medical ICU, we conducted a case–control study with matching for initial severity of illness, with daily monitoring of severity of illness and therapeutic activity scores, and with analysis of the contribution of nosocomial infections to patients' outcomes. Forty-one cases of patients who developed nosocomial infections during a 1-yr period were paired with 41 controls without nosocomial infection according to three criteria: age (± 5 yr), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (± 5 points), and duration of exposure to risk. Successful matching was achieved for 118 of 123 (96%) variables. Neurologic failure on the third day after ICU admission was the sole independent risk factor for nosocomial infection (adjusted odds ratio [OR]: 1.34; 95% confidence interval [CI]: 1.09 to 1.64; p = 0.007). Unlike control patients, case patients showed no clinical improvement and required a high level of therapeutic activity between ICU admission and the day of infection. Mortality attributable to nosocomial infection was 44%. Excess length of stay and duration of antibiotic treatment attributable to nosocomial infection were 14 d and 10 d, respectively. Attributable therapeutic activity as measured with the Therapeutic Intervention Scoring System (TISS) and Omega score was 368 and 233 points, respectively. Such consequences were observed in patients who developed multiple infections. These findings suggest that a persistent high level of therapeutic activity and persistent impaired consciousness are risk factors for nosocomial infections in ICU patients. These infections are responsible for excess mortality, prolongation of stay, and excess therapeutic activity resulting in important cost overruns for health-care systems.