Background: Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that maintains the typical features of C cells. An advanced stage and the presence of lymph node metastases at diagnosis have been demonstrated to be the most important bad prognostic factors. Somatic RET mutations have been found in 40–50% of MTCs. Although a relationship between somatic mutations and bad prognosis has been described, data are controversial and have been performed in small series with short-term follow ups. The aim of this study was to verify the prognostic value of somatic RET mutations in a large series of MTCs with a long follow up. Methods: We studied 100 sporadic MTC patients with a 10.2 yr mean follow-up. RET gene exons 10–11 and 13–16 were analyzed. The correlation between the presence/absence of a somatic RET mutation, clinical/pathological features, and outcome of MTC patients was evaluated. Results: A somatic RET mutation was found in 43 of 100 (43%) sporadic MTCs. The most frequent mutation (34 of 43, 79%) was M918T. RET mutation occurrence was more frequent in larger tumors (P = 0.03), and in MTC with node and distant metastases (P < 0.0001 and P = 0.02, respectively), thus, a significant correlation was found with a more advanced stage at diagnosis (P = 0.004). A worse outcome was also significantly correlated with the presence of a somatic RET mutation (P = 0.002). Among all prognostic factors found to be correlated with a worse outcome, at multivariate analysis only the advanced stage at diagnosis and the presence of a RET mutation showed an independent correlation (P < 0.0001 and P = 0.01, respectively). Finally, the survival curves of MTC patients showed a significantly lower percentage of surviving patients in the group with RET mutations (P = 0.006). Conclusions: We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.