© 2015 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved. Emerging evidence indicates that cancer-derived exosomes increase the tumorigenic potential of tumor cells by reprogramming the cells associated with the tumor microenvironment. Our aim was to examine the cross talk via exosomes between two oral squamous cell carcinoma (OSCC) clones from the same patient. Our data showed that exosomes derived from highly metastatic SQUU-B cells conferred metastatic ability to nonmetastatic SQUU-A cells and subsequently reduced mRNA expression of cytokeratin 13, which is strongly linked to malignant transformation of OSCCs. The results suggest that multiple cell clones secrete their unique exosomes within the malignant tumor mass, which mediate paracrine interactions with other cell clones and affect clinical prognosis.