Objective: In physiological conditions, the liver plays an important role in the regulation of plasma arginine concentrations by taking up large amounts of arginine from the hepatic circulation. When hepatic failure is present, arginine metabolism may be disturbed. Therefore, we hypothesized high arginine plasma concentrations in critically ill patients suffering from hepatic failure. Design: We prospectively collected blood samples from a cross-section of intensive care unit patients. Setting: Surgical intensive care unit of a Dutch university medical center. Subjects: A total of 52 critically ill patients with clinical evidence of dysfunction of more than two organs were recruited. Measurements: Plasma arginine concentrations were determined by HPLC. We identified correlations of arginine concentrations with organ failure scores and laboratory variables by univariate and multiple regression analyses. Results: High plasma arginine concentrations were found in critically ill patients developing organ failure. Patients who were in the highest quartile of plasma arginine concentrations had significantly lower fibrinogen concentrations, higher lactic acid concentrations, and longer prothrombin time. Stepwise multiple regression analysis showed that concentrations of arginine were independently associated with the presence of hepatic failure (P = 0.03) and renal failure (P = 0.048). In addition, lactic acid proved to be an independent determinant of plasma arginine concentration (P = 0.014). Conclusions: Critically ill patients who suffer from hepatic failure have elevated plasma arginine concentrations. Additional arginine in the treatment of these patients can be harmful, and therefore should not be used as a standard nutritional regimen until further evaluation.