WNT5A is a secreted signaling protein that promotes migration and invasion of oral squamous cell carcinoma (OSCC) cells through activation of non-canonical WNT signaling. Here, we examined expression of WNT5A, β-catenin, and E-cadherin by immunohistochemistry in 21 human diagnostic incision biopsies that each had regions of oral mucosa with a normal appearance adjacent to the affected tissue, dysplasia, and OSCC. We also investigated the effect of recombinant WNT5A (rWNT5A) on expression of the cell-adhesion proteins E-cadherin and β-catenin by western blot analysis. No expression of WNT5A protein was present in oral mucosa with a normal appearance or in mild grade dysplasia. However, expression of WNT5A increased along with increasing grade of dysplasia, and the highest expression was detected in OSCCs. Expression of membranous β-catenin and of E-cadherin was lower, whereas expression of cytoplasmic β-catenin was higher, in OSCCs than in non-cancerous regions. However, there was no correlation between expression of WNT5A and expression of either β-catenin or E-cadherin. Furthermore, treatment of OSCC cells with rWNT5A had no effect on the expression of β-catenin or E-cadherin. Taken together with previous results, we conclude that WNT5A influences the progression of OSCC without affecting the canonical WNT/β-catenin pathway and without down-regulating E-cadherin. WNT5A may have potential as a biological marker for malignant transformation of dysplasia to OSCC.