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Background Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. Aim To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. Methods This retrospective case–control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8, rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. Results In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41–0.72], P  < 0.0001]. Among inpatients with COVID-19 (n  = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n  = 187) (12% vs. 5%, OR 2.87 [1.42–5.78], P  = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P  < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r  = 0.19, P  = 0.01) and maximum CRP (r  = 0.16, P  = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. Conclusions In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7 MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7 MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection. [ABSTRACT FROM AUTHOR]