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Objective To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients. Methods Two functional polymorphisms in the MIF gene, a −794 CATT5-8 microsatellite repeat ( rs5844572) and a −173 G/C single-nucleotide polymorphism ( rs755622), were assessed for association with SLE in 3,195 patients and healthy controls. We also measured MIF plasma levels in relation to genotypes and clinical phenotypes, and assessed Toll-like receptor 7 (TLR-7)-stimulated MIF production in vitro. Results Both Caucasians and African Americans with the high-expression MIF haplotype −794 CATT7/−173*C had a lower incidence of SLE (in Caucasians, odds ratio [OR] 0.63, 95% confidence interval [95% CI] 0.53-0.89, P = 0.001; in African Americans, OR 0.46, 95% CI 0.23-0.95, P = 0.012). In contrast, among patients with established SLE, reduced frequencies of low-expression MIF genotypes (−794 CATT5) were observed in those with nephritis, those with serositis, and those with central nervous system (CNS) involvement when compared to patients without end-organ involvement ( P = 0.023, P = 0.005, and P = 0.04, respectively). Plasma MIF levels and TLR-7-stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. Conclusion These findings suggest that MIF, which has both proinflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage. [ABSTRACT FROM AUTHOR]