Macrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. W e explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identi fi ed among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated withMIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF’s protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-de fi cient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF- α, IL-12, IL-10). MIF-de fi cient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1 restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations. PNAS. 2013,110: 2997 –3006. Das R, Koo M, Kim BH, Jacob ST, Subbian S, Yao J, Leng L, Levy R, Murchison C, Burman WJ, Moore CC, Scheld WM, David JR, Kaplan G,. MacMicking JD, Bucala R. Department s of Medicine and Microbial Pathogenesis, Yale Scho ol of Medicine, New Haven, CT 06510. dasrit@mail.med.upenn.edu.