Introduction: Thyroid nodules are very common among general population. Most of them are benign, however thyroid cancer (TC) represents 5% of these nodules. PTC is the most prevalent malignant thyroid neoplasm and its diagnosis is dependent on the presence of specific nuclear features, however diagnostic difficulties may arise in some cases. CD56 is a neural cell adhesion molecule that is expressed in different immune cells and neurons. Previous researches reported that lack of this marker has been linked to the malignant potentiality of tumor cells. Aim of work: Evaluate the diagnostic value of CD56 in distinguishing benign from malignant thyroid lesions. Methods: Seventy tissue blocks representing benign and malignant thyroid lesions were randomly selected for the current study.  Among the forty selected malignant cases, 30 cases of papillary thyroid carcinoma and 10 cases of follicular carcinomas were included. Twenty cases of follicular adenomas and ten cases of nodular hyperplasia are included among the thirty benign lesions. Results: CD56 positive expression was found in 36 (51.4%) cases. A statistically significant relation was found between CD56 expression and histologic subtype and benign versus malignant lesions (p-value=<0.001 and <0.001 respectively). In PTC, CD56 negative expression was detected in 26 (86.7%) cases. A statistically significant relation was found between CD56 expression and site of lesion lymph node metastasis (p-value=0.029 and 0.009 respectively). Conclusion: CD56 can be a helpful immunohistochemical marker in distinguishing benign from malignant thyroid lesions.