Introduction: The pathological diagnosis of papillary thyroid carcinoma (PTC) is generally easy on routine sections stained with hematoxylin and eosin (H&E). However, the differentiation of the follicular variant of PTC (FVPTC) from other suspected follicular-patterned lesions of the thyroid is highly difficult. Among these, the lesions for which FVPTC cannot be excluded are classified as well-differentiated tumors of uncertain malignant potential (WDT-UMP). The most common immunohistochemical (IHC) markers used in the differential diagnosis include HBME-1, galectin-3, and CK19. However, none of these markers provide a 100% differential diagnosis. Objective: The present study compared the diagnostic value of CD56 and E-cadherin for the differentiation of FVPTC from the other benign follicular-patterned lesions, with HBME-1, galectin-3, and CK19. Using these markers, the controversial cases within the WDT-UMP group were reclassified. Additionally, the relationship between the reductions in E-cadherin expression with poor prognostic factors was investigated. Materials and methods: The IHC expressions of CD56, E-cadherin, HBME-1, galectin-3, and CK19 were evaluated in 181 thyroid lesions, including 101 PTCs (45 classical variant PTCs and 56 FVPTCs), 20 WDT-UMPs, 20 follicular adenomas (FAs), 20 hyperplastic nodules (HN), and 20 hyperplastic foci of lymphocytic thyroiditis. The results were statistically compared via SPSS. Results: The expressions of all of the markers were statistically significantly different in PTC and follicular-patterned lesions (P<0.05). It was found that the only marker with both sensitivity and specificity above 90% was CD56 negativity (sensitivity 91.1%, specificity 91.7%). The most sensitive and also the most specific double panel was CD56 negativity and galectin-3 positivity (sensitivity 96%, specificity 85%), and the most sensitive and specific triple panel was CD56 negativity, HBME-1 positivity, and galectin-3 positivity (97% and 70%, respectively).