Objective: To investigate the role of macrophage migration inhibitory factor (MIF) as a marker of severity of systemic inflammation in patients with severe sepsis and critically ill postsurgical patients. Design: Prospective observational study in consecutive patients with severe sepsis, critically ill nonseptic postsurgical patients, and healthy blood donors. Setting: A surgical intensive care unit of a university hospital. Patients and participants: 19 patients with severe sepsis, 18 critically ill nonseptic postsurgical patients, and 10 healthy blood donors. Measurements and results: MIF plasma levels of patients and participants were measured. Interleukin 6 plasma levels were monitored as a control marker of inflammation. The median MIF plasma level was four to five times higher in patients with severe sepsis (2.70 ng/ml, range 0.31–19.59) and in critically ill nonseptic postsurgical patients (2.43 ng/ml, range 0.49–4.31) than in healthy blood donors (0.56 ng/ml, range 0.16–1.68). MIF plasma levels did not differ between the patient groups. Conclusions: MIF serves as a general marker for systemic inflammation in septic and nonseptic acute critical illness, but MIF does not discriminate for severity or differentiate between infectious and noninfectious origins of an acute critical illness.