Oxidative stress, a situation with increased reactive oxygen species production and/or decreased antioxidant defense mechanisms, is evident in the pathogenesis of sepsis. Peroxiredoxin 4 (Prx4) is a hydrogen peroxide degrading peroxidase recently found circulating in blood of septic patients and potentially reflecting an antioxidant system in imbalance. We studied Prx4 serum levels of 79 consecutively enrolled medical intensive care unit patients. The diagnostic and prognostic performance of Prx4 was compared with other biomarkers, the APACHE II score and the SOFA score. Median Prx4 serum levels gradually increased with disease severity in patients classified on admission as having systemic immune response syndrome (2.32 arbitrary [arb.] U/L), sepsis (5.02 arb. U/L), severe sepsis (11.7 arb. U/L), or septic shock (11.4 arb. U/L). A positive correlation was found with the severity score Acute Physiological and Chronic Health Evaluation II (r = 0.27, P < 0.05) and the organ failure score Sequential Organ Failure Assessment (r = 0.55, P < 0.0001). Peroxiredoxin 4 correlated with the sepsis marker procalcitonin (r = 0.61, P < 0.0001), the inflammatory markers C-reactive protein (r = 0.65, P < 0.0001) and interleukin 6 (r = 0.62, P < 0.0001), and antioxidant blood compounds total bilirubin (r = 0.37, P < 0.001) and albumin (r = -0.54, P < 0.0001). Peroxiredoxin 4 distinguished noninfectious from infectious inflammatory response syndrome with an area under the receiver operating characteristic (ROC) curve of 0.82. [corrected] High Prx4 serum levels were associated with a poor prognosis of septic patients and revealed an area under the ROC curve of 0.76 in prediction of in-hospital mortality. In this study, elevated serum levels of the antioxidant Prx4 were associated with an increased disease severity and adverse outcome of critically ill patients with sepsis. Peroxiredoxin 4 may therefore be a helpful new biomarker for diagnosing, monitoring, and risk assessing these patients. The pathophysiological mechanisms behind the observed increase remain to be elucidated.