In multiple endocrine neoplasia syndrome Type 2 (MEN2), medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) are associated with hereditary activating germ‐line mutations in the RET proto‐oncogene. Also in a large percentage of sporadic MTCs and PCs, somatic RET mutations appear to be involved in tumor formation. In one single MEN2 family an extensive variety in disease expression may be observed, indicating that additional genetic events are responsible for progression of the disease towards a more aggressive phenotype. However, these additional mutations in both hereditary and sporadic MTC and PC development are largely unknown. Here, we show for the first time the presence of somatic mutations in the cell cycle regulator P18 in human RET‐associated MTCs and PCs. Each of these mutations causes an amino acid substitution in the cyclin dependent kinase‐interacting region of P18^INK4C. Since these mutations partly inhibited P18^INK4C function and reduced its stability, our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development. © 2008 Wiley‐Liss, Inc.