Medullary thyroid carcinoma can have an aggressive behavior, and little is known about the molecular basis for clinical outcome. Defining risk of recurrent or metastatic disease is difficult, and it has been limited to clinical and pathologic features, such as advanced age, cervical lymph node metastases, and stage at presentation. Using microdissection and genotyping, we studied 11 cases of medullary carcinoma for allelic losses in a panel of known tumor suppressor genes. The tumor suppressor genes with the most frequent allelic losses were NF2, l-myc, and p53 (75%, 44%, and 44%, respectively). The average frequency of allelic loss across all tumors was 44% and was higher in tumors that recurred. A combination of previously described high-risk variables (increased patient age and cervical lymph node metastases) with the frequency of allelic loss yielded a high-risk group, in which 6 of 6 patients recurred, and a low-risk group, in which 0 of 5 patients recurred (P = 0.004). Frequency of allelic loss in tumor suppressor genes may provide a useful adjunctive prognostic test in medullary thyroid carcinoma.