Objective: To determine the relations between macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and cortisol in patients with systemic inflammatory response syndrome (SIRS) and to determine whether their levels correlate with patient survival. Design: Prospective, observational, cohort study. Setting: General intensive care unit in a university hospital. Patients and participants: The study included 17 consecutive patients who met the criteria for SIRS; the patients were classified into subgroups, survivors (n = 8) and nonsurvivors (n = 9); eight healthy volunteers served as control subjects. Interventions: None. Measurements and results: Serum MIF, TNF-α, IFN-γ, and cortisol levels were measured serially when the patients were first identified as having SIRS (day 0), and on days 1–4. Except for the high tendency of acute respiratory distress syndrome in nonsurvivors (44%) compared to survivors (13%), there were no differences in the clinical backgrounds of the patients between the two groups. All patients had multiple organ dysfunction syndrome. The values of MIF and TNF-α in the nonsurvivors were significantly more elevated than those cytokines measured in the survivors and control subjects. Peak MIF levels significantly correlated with peak TNF-α levels (r ² = 0.448, P = 0.002), but did not correlate with peak levels of cortisol and IFN-γ. Although the levels of IFN-γ and cortisol showed a marked increase compared to those of the control subjects, we could not find differences in these variables between the survivors and the nonsurvivors. Conclusions: High MIF and TNF-α levels are closely linked with poor outcome in patients with SIRS. MIF and TNF-α may act together and have pathogenic roles in SIRS.