Macrophage migration inhibitory factor (MIF) is a pleiotrophic lymphocyte and macrophage cytokine; it is likely to play an important role in innate immunity. Genome-wide search for atopy susceptibility genes recently identified human chromosome 22q11, where the gene encoding MIF resides, as a region of interest for atopic traits. Both the -173G/C and -794 [CATT]5-8 repeat polymorphisms in the MIF promoter region are associated with altered levels of MIF gene transcription in vitro. We, therefore, hypothesized that these potentially functional polymorphisms may influence susceptibility to atopy and asthma. A case-control analysis examined the genetic influence of these promoter polymorphisms on the development of atopy and asthma in a Japanese population (n = 584). Evidence for significant association between the -173G/C and -794 [CATT]5-8 repeat polymorphisms and atopy was found; odds ratio for homozygotes of -173C allele was 3.67 (compared with homozygotes of -173G allele, 95% confidence interval = 1.43-9.46, p < 0.01), and odds ratio for noncarriers of the -794 [5-CATT] allele was 3.51 (compared with 5-CATT repeat homozygotes, 95% confidence interval = 1.82-6.78, p < 0.0005). No associations with asthma were detected. These results indicate that promoter polymorphisms in the MIF promoter region are risk factors for atopy and implicate MIF in the pathogenesis of atopy in a Japanese population.