EpCAM is a cell-adhesion molecule, located at the basolateral membrane of the normal epithelial cells. Changes in EpCAM expression are reported in several malignancies, as an early indicator for carcinogenesis. Our study aimed to evaluate the EpCAM expression in different subtypes of papillary thyroid carcinoma (PTC), focusing on its role in the risk stratification of the histological variants and its relationship with the classical clinico-pathological characteristics. We analyzed 70 selected cases of PTC, divided into low- and high-risk groups, according to histological criteria. Immunohistochemical (IHC) exam was performed using MOC-31 antibody, against the EpEx-MOC-31 extracellular domain of EpCAM molecule. MOC-31 expression was assessed at the membrane and cytoplasmic levels, using a semi-quantitative score that allowed the classification in low- and high-score category, respectively. The relationship between MOC-31 expression and clinico-pathological characteristics was statistically evaluated. We found statistically significant correlation between MOC-31 expression (low versus high) and the risk groups, tumor size and tumor relapse. The twofold analysis, based on score system and risk category, showed an association between low score and low risk in 80% of all cases, low score and high risk in 56% of the cases, high score and low risk in 36% of the cases and high score and high risk in 44% of the cases. The modification of MOC-31 location, with consequent changes in its interactions with other cell-adhesion molecules, is integrated in the carcinogenic mechanism. Our study demonstrates the large variability of MOC-31 expression in PTC histological variants, and highlights the differences between the low and high MOC-31 expression that could work as a useful tool for the identification of those high-risk PTC cases, with unfavorable clinical outcome.