Objective: To investigate the concentration of cell- free plasma DNA and its association with organ dysfunction and hospital mortality in intensive care unit patients. Design and setting: Prospective cohort study in a medical and two medical- surgical intensive care units in a university hospital. Patients: 228 critically ill patients admitted to the ICUs between January 2004 and July 2005. Measurements and results: Blood samples were collected as soon as possible after ICU admission, the following morning, and 48 h after the second sample. The cell- free plasma DNA was measured by real- time quantitative PCR assay for the beta- globin gene. Physiological and mortality data were collected to the clinical database. Hospital mortality rate and SOFA scores were primary outcome measures. The maximum plasma DNA concentrations were correlated significantly with APACHE II points and with maximum SOFA scores. Cell- free plasma DNA concentrations were higher in hospital non- survivors than in survivors ( median 9,366 vs. 6,506 GE/ ml). Using logistic regression analysis, the maximum plasma DNA was an independent predictor of hospital mortality. Conclusions: The maximum plasma DNA concentration measured during the first 96 h of intensive care is associated with the degree of organ dysfunction and disease severity. Moreover, the maximum DNA concentration is independently associated with hospital mortality.