OBJECTIVE: Macrophage migration inhibitory factor (MIF), a protein secreted by immune cells and the pituitary gland, may be associated with coronary artery disease (CAD) and the mental state of coronary patients. The first origin of MIF suggests positive, the second negative associations. The aim of this study was to explore the direction of the association of MIF with CAD and of MIF with exhaustion, if any. METHODS: Participants were 194 patients who had been recently treated by percutaneous coronary intervention (PCI) and who were exhausted at the start of the study. Half entered a behavioral intervention program. MIF, C-reactive protein, interleukin (IL)-6, IL-1 receptor antagonist, and neopterin were measured in blood collected 6 weeks after PCI (baseline) and 6 and 18 months after baseline. A single measurement of MIF was also available for 129 age- and sex-matched healthy individuals (reference group). RESULTS: At baseline, MIF in patients undergoing PCI was significantly lower than in the reference group (p < .01). New cardiac events occurred twice as often in the lowest quartile than in the highest quartile of MIF concentrations. However, the association was not significant (chi(2) = 2.27; df = 3; p = .52). During follow up, MIF concentrations increased significantly in patients undergoing PCI (p < .001). At 18 months, MIF concentrations were significantly lower in the exhausted patients than in the nonexhausted patients (p = .02). hsCRP, IL-1ra, IL-6, and neopter in concentrations did not change over this time period. CONCLUSIONS: The data are suggestive of a negative association of MIF with CAD and of MIF with exhaustion. The observation that those patients who remained exhausted had lower concentrations of MIF fits into earlier observations that suggested that exhausted coronary patients may be characterized by a hypoactivity of the hypothalamic-pituitary-adrenocortical axis.