We hypothesized that circulating levels of lipid peroxidation products in patients with severe sepsis are associated with the development of pulmonary, renal, hepatic, circulatory, and coagulation failure. Plasma levels of F2-isoprostanes and isofurans were measured by mass spectroscopy on intensive care unit day 2 in 50 critically ill patients with severe sepsis. Plasma F2-isoprostane levels were higher in patients who developed renal failure compared with those who did not (65 pg/mL [interquartile range {IQR} 44-112] vs. 44 pg/mL [IQR 29-54], P = 0.009) as were isofuran levels (1,223 pg/mL [IQR 348-2,531] vs. 329 pg/mL [IQR 156-1,127], P = 0.009). Plasma F2-isoprostane levels were higher in patients who developed hepatic failure compared with those who did not (72 pg/mL [IQR 44-112] vs. 44 pg/mL [IQR 30-65], P = 0.023), and there was also a trend for higher isofuran levels (1,411 pg/mL [IQR 298-1,965] vs. 525 pg/mL [IQR 160-1,223], P = 0.14). Coagulation failure (thrombocytopenia) was associated with higher isofuran levels. Circulatory failure and acute lung injury were not associated with elevated levels of isoprostanes or isofurans. Patients with isoprostane levels above the 25th percentile had higher mortality (42%) compared with patients with levels below the 25th percentile (8%, P = 0.03). Plasma levels of F2-isoprostanes and isofurans are associated with renal, hepatic, and coagulation failure, but not with circulatory or pulmonary failure in severe sepsis, suggesting that lipid peroxidation is a prominent feature of septic multisystem organ failure. Plasma isoprostanes and isofurans may be useful for monitoring oxidative stress in treatment trials of antioxidant therapies in severe sepsis.