Abstract. The aim of this study is to determine the utility of galectin-3 and HBME-1 in the differentiation between benign and malignant thyroid lesions. We evaluated the immunohistochemical expression of 64 thyroid lesions including non-neoplastic lesions and neoplastic lesions. Galectin-3 immunostaining was positive in 100% of papillary carcinomas, 62.5% of follicular carcinomas, 18.8% of follicular adenomas and negative in all nodular goiter as non -neoplastic lesions. HBME-1 immunostaining was positive in 93.8% of papillary carcinomas, 81.3% of follicular carcinomas, 25% of follicular adenomas and negative in all nodular goiter. There was a significant difference between benign and malignant thyroid lesion for galectin-3 and HBME-1 (p<0.001). The sensitivity, specificity, positive predictive values and negative predictive values for HBME-1 and galectin-3 is over 80%. When both markers are combined, the values of each predictive parameter were 93.75%, 81.25%, 83.33% and 92.85%. The diagnostic accuracy for both markers was 87.50%. Combining both markers will be more helpful to differentiate malignant and benign thyroid lesions.