In patients with septic shock (n = 32), multitrauma (n = 8), and hospitalized matched controls (n = 41), we serially measured serum macrophage inhibitory factor (MIF), cortisol, plasma ACTH, tumor necrosis factor-alpha, and interleukin-6 (IL-6) immunoreactivity during 14 days or until discharge/death. MIF levels were significantly elevated on day 1 in septic shock (14.3 +/- 4.5 microg/L), as opposed to trauma (3.1 +/- 1.7 microg/L) and control patients (2.5 +/- 2.1 microg/L). The time course of MIF, parallel to cortisol, but in contrast to ACTH, showed persistently elevated levels in septic patients. On admission, nonsurvivors of septic shock (n = 11) showed significantly higher MIF levels than survivors (18.4 +/- 4.8 and 10.2 +/- 4.2 microg/L, respectively). Patients with septic adult respiratory distress syndrome (ARDS; n = 8) showed higher MIF levels than those who did not develop ARDS (19.4 +/- 4.7 vs. 9.2 +/- 4.3 microg/L, respectively). Multiple logistic regression analysis demonstrated that both MIF and ARDS were independent predictors of adverse outcome. On admission, tumor necrosis factor-alpha, IL-6, procalcitonin, and lipopolysaccharide-binding protein levels were higher in patients with septic shock than in patients with multitrauma. In septic patients, regression analysis showed significant correlations between MIF and cortisol as well as between MIF and IL-6 levels and disease severity scores. No relation was found between MIF and markers of the acute phase response (procalcitonin, C- reactive protein, and lipopolysaccharide-binding protein). In multitrauma patients, MIF levels were not elevated at any time point and were not related to other variables. Our data suggest that during immune-mediated inflammation (such as septic shock) MIF is an important neuroendocrine mediator: a contraregulator of the immunosuppressive effects of glucocorticoids.