Systemic levels of the key immune regulatory cytokines IL-12 and IL-18 were measured over time in 66 patients with postoperative sepsis (38 survivors and 28 nonsurvivors). Sepsis mortality was not significantly associated with any of the clinical parameters examined, including age, gender, underlying disease, and surgical procedure. Analysis of cytokine levels showed that during the entire observation period, IL-12 was significantly reduced in sepsis patients compared with control surgical patients without sepsis. IL-12 serum levels did not significantly differ between sepsis survivors and nonsurvivors. In contrast to IL-12, IL-18 serum levels were significantly higher in both surviving and nonsurviving sepsis patients than in controls. Importantly, we also observed that IL-18 levels were significantly increased in patients with lethal sepsis compared with sepsis survivors at all time points studied, including day 1 after sepsis diagnosis. IL-18 levels were significantly increased during the course of lethal sepsis, but remained at a comparable level in sepsis survivors. Logistic regression analysis of IL-18 values measured on days 1 or 2 of sepsis revealed that high serum IL-18 represents an early predictive factor for the lethal outcome of postoperative sepsis. Consistent with previous work in mouse models, our results suggest that IL-12 may contribute to protective immune reactions against a septic challenge, whereas IL-18 may preferentially promote organ injury and lethal shock.