Graves' disease (GD) is caused by an interplay of genetic factors and environmental triggers. The major antigen in GD is the thyrotropin receptor (TSHR) on the surface of the thyroid epithelial cell. Population-based case-control studies have largely shown no association of GD with the D36H (Asp to His) and P52T (Pro to Thr) single nucleotide polymorphisms (SNPs) in the N-terminal region of the extracellular domain of the TSHR gene in Caucasian populations. Recently, a D727E (Asp to Glu) SNP in the intracellular C-terminal domain of the TSHR was reported to be associated with GD in a Russian population. In the present study we assessed whether the codon 727 SNP is associated with GD in a Caucasian population. We found no significant differences in codon 727 SNP frequencies between GD patients and controls. In addition, our results did not show an effect of the SNP on the GD phenotype and on disease severity. Further analysis showed no evidence that the TSHR 727 SNP modulated the risk for GD conferred by HLA (DR3) and/or CTLA-4 (SNP 49 G allele) genes. A meta-analysis combining our data and those of 2 previous studies showed a very weak association between the D727E SNP and GD (p = 0.03, relative risk = 1.6). Therefore, we concluded that the TSHR gene is not a major gene for GD in our population.