Background The diagnosis of suspicious lesions in thyroid is based mainly on histological examination. Follicular pattern in thyroid is shared by different lesions that have different prognosis. The overlap between the follicular lesions is common. Malignant follicular lesions include follicular variant of papillary thyroid carcinoma (FVPTC) that has better prognosis than follicular carcinoma (FC). Aim To evaluate claudin-1 and cytokeratin 17 (CK17) immunostains as useful diagnostic markers for malignant follicular thyroid lesions. Materials and methods Sixty-six cases of different thyroid lesions were submitted for immunohistochemical staining of claudin-1 and CK17. Sensitivity, specificity, positive predictive value, and negative predictive value were analyzed. Results Claudin-1 expression was detected in 100% of the FVPTC, 90% of FC cases, 23.1% of follicular adenoma, 20% of colloid goiter, and 14% of Hashimoto thyroiditis cases. The difference between claudin-1 expression in benign thyroid lesions and thyroid carcinomas was significant (P=0.001 for each), whereas it was insignificant (P=0.3) between FVPTC and FC. CK17 was expressed in 75% of FVPTC, 90% of FC, 23.1% of follicular adenoma, and 28.6% of Hashimoto thyroiditis and totally absent in colloid goiter. The difference in frequency of CK17 positivity between FVPTC and benign thyroid lesions was statistically significant (P=0.001). The difference was also significant (P=0.001) between FC and benign thyroid lesions. It was insignificant between FC and FVPTC (P=0.6). Comparing malignant thyroid lesions with other benign follicular lesions, CK17 provided 80.0% sensitivity and 83.3% specificity, whereas claudin-1 provided 96.7% sensitivity and 80% specificity for identification of thyroid carcinoma. The combined use of both markers did not increase the diagnostic accuracy. Conclusion The use of claudin-1 and CK17 can be valuable in differentiating thyroid carcinoma from other mimicking benign thyroid follicular lesions, but they cannot help in segregating types of thyroid cancer. Egypt J Pathol 38:241–248 © 2018 Egyptian Journal of Pathology.