Abstract: In this study, we investigated the distribution of the standard form of the CD44 (CD44s) cell adhesion molecule and of its v3 and v6 isoforms in samples of foetal and adult parotid gland tissue, in comparison with samples of parotid gland adenomas and carcinoma ex pleomorphic adenoma. Foetal parotid gland showed CD44s and CD44v3 expression in the peripheral small primordial ducts and acini, while CD44v6 was only focally expressed. Adult parotid gland tissue showed a similar distribution of CD44s and variants, with a predominant expression in acinar structures and a weaker expression at duct level. In parotid gland adenomas, a diffuse and intense expression of CD44s and variants 3 and 6 was observed only in pleomorphic adenomas, while expression of CD44s was prevalent in Warthin’s tumour, myoepithelioma and oncocytoma. The malignant areas of carcinoma ex pleomorphic adenoma showed a markedly decreased expression of CD44v3 and CD44v6 in comparison with the adjacent pleomorphic adenoma component. In conclusion, the prevalent expression of CD44s and variants in pleomorphic adenoma in comparison with other adenomas may be related to the abundant extracellular matrix production present in these tumours, while loss of CD44v3 and CD44v6 associated with the onset of carcinoma ex pleomorphic adenoma could promote stromal invasion, eventually contributing to the development of distant metastases.