Many single nucleotide polymorphisms (SNPs) of the RET gene have been described both in the general population and in patients with sporadic medullary thyroid cancer (sMTC), MEN2 or Hirschsprung disease. Some association studies reported a higher prevalence of these variants in the affected patients, suggesting a possible role in modifying the risk of occurrence of the disease. However, data from different cohorts of sMTC are discrepant and the aim of the present study was to determine if a variant per se or a combination of variants predispose to sMTC. Thus, a possible association of RET haplotype(s) and disease was looked for in 82 patients affected with sMTC and 49 age matched controls. Six RET SNPs were studied by PCR and direct sequencing. The most frequent SNPs were those in intron 1 (30 and 32% in sMTC and controls, respectively), exon 2 (22 and 24%) and exon 13 (24 and 26%). No significant differences were observed in the prevalence of single SNPs between patients and controls, including G691S, which is the only non-synonymous variant. Accordingly, functional analyses did not reveal an increased autophosphorylation for G691S. Twelve unique haplotypes, labelled A-N, were obtained. The distribution of haplotypes between cases and controls were significantly different (P<0.05). The study of the association of these different haplotypes in cases and controls lead to the identification of 30 different genotypes. Inspection of the genotypes in the two groups showed that the genotype distribution between cases and controls was different (P<0.05). In particular, there were 7 genotypes unique to controls, 13 unique to sMTC and 11 shared by the 2 groups. For example, AA, AC, AD and AH, all of which containing one allele without polymorphisms, are prominently or uniquely represented in sMTC. These data suggest that genotypes comprising specific pairs of RET haplotypes are associated with predisposition to sMTC. In this series, the absence on both alleles of the 6 SNPs analyzed was recorded only for MTC cases, indicating that the presence of RET variants could be protective against cancer development.