Purpose: Thyroid cancer is the most frequently occurring endocrine malignancy; however, preoperative diagnosis of same lesions, in particular those with follicular histology, is difficult, and a consistent number of not-otherwise specified "follicular nodules" are surgically resected more for diagnosis than therapeutic purposes. In this study we investigated whether the lectin-related molecules CD44v6 and galectin-3, the expression of which is altered during deregulated cell growth and malignant transformation, could be potential markers for improving the diagnostic accuracy of conventional cytology, Materials and Methods: A comparative immunochemical and molecular analysis was performed on 157 thyroid specimens representative of normal, benign, and malignant tissues, and on 36 cytologic samples obtained preoperatively by fine-needle aspiration biopsy from nonselected patients with palpable thyroid nodules. Results: Normal thyrocytes did not express galectin-3 nor CD44v6. Although the expression of CD44v6 is negligible in thyroiditis, there molecules are variably detected in benign and malignant proliferative lesions. interestingly, galectin-3 is never expressed in benign lesions, but is invariably detected in cancers, A comparative evaluation of CD44v6 and galectin-3 expression in thyroid malignancies demonstrated that these molecules ore coexpressed at the messenger RNA and protein lever in almost all lesions, Conclusion: Our findings suggest that CD44v6 and galectin-3 could be potential markers to preoperatively identify malignant transformed thyrocytes, Immunodetection of these molecules on cytologic specimens obtained by fine-needle aspiration biopsy is an accurate and improved method for selecting, on a molecular basis, there nodular lesions of the thyroid gland that need to be surgically resected, (C) 1999 by American Society of Clinical Oncology.