Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germ-line missense mutations in the RET proto-oncogene. Only a minor fraction of human disorders are simple monogenic diseases, and the identification of polymorphisms that increase susceptibility, including variations in pathological phenotypes, to human diseases is one of the key problems in medical genetics. To explore this idea, we analyzed the polymorphisms G691S (exon 11) and S904S (TCC-TCG, exon 15) of RET in 198 individuals corresponding to 35 unrelated Spanish MEN 2A families (104 patients with oncogenic MEN 2A mutation and 94 healthy relatives). We found strong cosegregation between both polymorphisms (100% Fisher's exact test, P < 0.001) using a control population containing 653 healthy individuals (362 females and 291 males). Interestingly, we found that the homozygous for these polymorphisms were, on average, 10 years younger at diagnosis compared with heterozygous and wild-type homozygous (P = 0.037). Taken together, all these findings could indicate that the G691S and S904S variants of RET have a modifier effect on the age at onset of MEN 2A. Moreover, compared with the control population, the homozygote status was significantly more prevalent in a series of 110 sporadic thyroid carcinoma (odds ratio = 2.36), suggesting that these polymorphisms may play a role as a low penetrance risk factor.