Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms (–794 CATT_5–8 microsatellite and –173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT₅ allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001), which increased in correlation with the CATT₅ copy number (P=0.04). The CATT₅ allele, but not the —173 G/C alleles, was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2‐6.4), P=0.02]. A family‐based association test (i.e., transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT₅ was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP‐1 monocytic cells or in a whole‐blood assay, CATT₅ was found to be a low‐expression MIF allele (P= 0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together, these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence, severity, and outcome of meningococcal disease in children.—Renner, P., Roger, T., Bochud, P.‐Y., Sprong, T., Sweep, F. C. G. J., Bochud, M., Faust, S. N., Haralambous, E., Betts, H., Chanson, A.‐L., Reymond, M. K., Mermel, E., Erard, V., van Deuren, M., Read, R. C., Levin, M., Calandra, T. A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease. FASEB J. 26, 907–916 (2012). www.fasebj.org