Microtubule-associated protein 2 (MAP2) has been better known for its well-defined role primarily in neurite outgrowth during neuronal development. However, the biological functions of MAP2 in non-neuronal cells, such as epithelial cells, remain largely unknown. In the present study, we sought to investigate the cellular functions of MAP2 by separately establishing stable expression of two MAP2 isoforms, MAP2A and MAP2C, in oral squamous cell carcinoma, Ca9-22. Ectopic expression of MAP2A or MAP2C results in microtubule bundling predominantly at the cell periphery. Remarkably, overexpression of MAP2A but not MAP2C significantly promotes migration of Ca9-22 cells, whereas knockdown of MAP2A expression by specific siRNA oligos dramatically decreases cell migration of HaCaT, an immortalized keratinocyte cell line with abundant endogenous MAP2A. Furthermore, by immunohistochemical studies, MAP2A was shown to highly and selectively express in invasive oral cancer tissues, consistent with its motility-promoting cellular function revealed through in vitro assays. Thus, our findings have not only identified a novel role of MAP2 in non-neuronal cells, but also provided the first implication of MAP2 in malignant oral cancer tissues.