Graves disease (GD) is an autoimmune disease. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Two polymorphisms in the promoter region of MIF, rs5844572 and rs755622, are known to affect MIF expression. The purpose of this study was to investigate the relationship between polymorphisms in the MIF gene promoter and the severity of GD. A total of 677 individuals, including 481 GD patients and 196 ethnically matched healthy controls, were genotyped to identify differences in the distribution of the MIF polymorphisms rs5844572 and rs755622. Although there were no significant differences in the allele or genotype distributions among patients with different grades of goiter in GD and healthy controls, the distribution of the C allele, especially C/C genotype, of the rs755622 single nucleotide polymorphism (SNP) in MIF, may be as a risk factor for goiter initiation whereas a protector against development of severe goiter in patients with untreated GD (p<0.05). A goiter-developmental model incorporating genetic (MIF SNP rs755622) and environmental risk factors (gender, radioiodine treatment, thyroid gland surgery and vitiligo) significantly increased the prediction accuracy. Further studies are required to address the role of MIF polymorphisms, as well as their association with other candidate genes, in GD.