OBJECTIVE To determine whether plasma levels of macrophage migration inhibitory factor, a proinflammatory cytokine involved in atherogenesis, are predictive of myocardial infarction or death from coronary artery disease. METHODS We performed a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. We selected men and women who did not report a history of myocardial infarction or stroke at baseline. Baseline concentrations of macrophage migration inhibitory factor were measured among 777 patients who had a myocardial infarction or died of coronary artery disease during follow-up, and 1554 matched controls who remained free of coronary artery disease. RESULTS Baseline macrophage migration inhibitory factor concentrations were higher in cases than controls (median, 107.4 microg/L vs. 90.7 microg/L, P = 0.001). The risk of myocardial infarction or death from coronary artery disease increased with increasing quartiles of macrophage migration inhibitory factor (P for linearity <0.0001). Patients in the highest quartile had the greatest likelihood of myocardial infarction or death due to coronary artery disease (unadjusted odds ratio [OR] = 1.6; 95% confidence interval [CI]: 1.2 to 2.0). After adjustment for traditional risk factors and C-reactive protein level, the odds ratio decreased slightly (OR = 1.3; 95% CI: 1.0 to 1.7). Upon additional adjustment for white cell count, this association was no longer statistically significant. CONCLUSIONS Prospective data suggest that the relation between macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without a history of myocardial infarction or stroke is not very strong. However, the data support a regulatory role for macrophage migration inhibitory factor in the process of atherosclerosis.