The change in the expression pattern of CD44 variant 6 (CD44v6) protein in benign, premalignant, and malignant (SCC) oral epithelial lesions was studied immunohistochemically and compared with the pattern in normal mucosa in order to examine whether this gene can serve as a progression marker in patients with SCC. The principal finding is that CD44v6 expression was clearly downregulated in most cases of severe premalignant lesions as well as in most of the SCCs. The staining pattern and intensity varied according to the degree of dysplasia and to the degree of differentiation of the SCCs. Premalignant severe epithelial dysplasia cases with early features of invasion, not yet developed into SCC, showed distinctly downregulated expression of CD44v6 protein whereas hyperplastic and benign epithelial lesions (papilloma) expressed positive staining patterns comparable to those of the normal counterparts. The authors conclude that alteration in CD44v6 may occur as an early event in primary oral SCC development, as well as in premalignant severe epithelial dysplasia. It can thus, be used as a molecular progression marker when screening for oral cancer.