BACKGROUND: A member of the genes encoding WD-repeat proteins, the WDR3 gene, maps in the 1p12 region. This region was shown to be associated with thyroid cancer susceptibility in a previous work. In this study we aim to evaluate the contribution of WDR3 to thyroid cancer risk. METHODS: A case-control association study was performed in a total of 402 patients and 479 control subjects from a Spanish population. In the initial phase of the study, 10 single-nucleotide polymorphisms covering the WDR3 region were genotyped in a small group (157 patients and 118 control subjects); next, three of the initial single-nucleotide polymorphisms were further genotyped in the overall population. In addition, WDR3 expression was investigated in 10 thyroid cancer cell lines by RT-PCR and Western blot. RESULTS: Haplotype analysis revealed that combination of certain WDR3 variants, such as haplotype CAT, increases the risk of thyroid cancer (odds ratio = 1.85, 95% confidence interval = 0.97-3.55, p = 0.063). Further, both messenger RNA transcription and protein expression of WDR3 were altered in human thyroid cancer cells. CONCLUSION: These results indicate for the first time that WDR3 is a risk factor to thyroid cancer, suggesting its implication in the etiology of thyroid cancer.