Tenascin C (Tn-C) is an extracellular matrix glycoprotein that is expressed early in carcinogenesis including intraepithelial neoplastic lesions of different organs. In this study, we analyze whether stroma reaction seen by Tn-C expression is detected early in tumorigenesis of medullary thyroid carcinoma (MTC) including medullary microcarcinoma and C-cell hyperplasia (CCH), which is accepted to be a precursor lesion of MTC in the setting of RET oncogene germ-line mutation. Tn-C was expressed in the stroma of all medullary microcarcinoma and in the stroma next to CCH. Stromal Tn-C expression was significantly more often seen in CCH with concomitant MTC than in isolated CCH of hereditary as well as nonhereditary cases (p = 0.001 and p = 0.016, respectively). We conclude that Tn-C expression and thus early stroma remodeling is seen in medullary microcarcinoma and CCH. Stromal Tn-C expression seems to be an indicator of a further step in carcinogenesis of MTC irrespective of a RET oncogene germ-line mutation.