Graves' disease (GD) is influenced by two major susceptibility loci, HLA-DR3 and thyroglobulin (Tg). Recently we have shown that specific HLA-DR and Tg gene sequences predispose to Graves' disease. Individuals carrying at least one arginine at position 74 of the DRbeta1 chain (denoted the R- genotype) have a significantly increased risk of GD, as do individuals homozygous for the single nucleotide protein (SNP) in exon 33 of the Tg gene (denoted the CC genotype). Therefore, for the current study we hypothesized that these two genes may interact to influence the etiology of GD. To test this hypothesis, we analyzed the genotypes of 185 Caucasian patients with GD and 143 Caucasian controls for both genes. We tested for an interaction effect, that is, is one gene's effect on GD greater when the other gene is also present than when the other gene is absent? A logistic regression analysis yielded an estimate of 4.31 for the interaction term (p = 0.053). Our results may suggest an interaction between the R- and CC variants in conferring susceptibility to GD. These results, if confirmed, may imply that these two variants interact biologically to increase the odds of GD.