Background. This article sought to investigate the existence of parameters useful for predicting lymph node metastases in cases of surgically resected oral squamous cell carcinomas (OSCCs). Methods. Fifty-eight cases were studied for E-cadherin and the truncated dominant-negative isoform of p63 (Delta Np63) with immunohistochemistry. In addition, the p63 gene expression profile was evaluated by reverse transcriptase-polymerase chain reaction (RTPCR) to disclose the presence of the truncated variant Delta Np73L. Results. E-cadherin expression was the most powerful parameter related to the presence of lymph node metastases at presentation. Twenty-four of 38 (63%) cases showing low E-cadherin expression had lymph node metastases at presentation compared with 5 of 20 (25%) (p <.01) cases showing high E-cadherin expression. The high predictive value was also maintained when a low expression of E-cadherin was associated with immunohistochemical high expression of Delta Np63. The association between low E-cadherin expression and Delta Np73L (as seen with reverse transcriptase-polymerase chain reaction) was highly predictive for developing lymph node metastases, especially in small tumors (T1\T2). When this association occurred, metastases developed in 62.5% of cases during the follow-up compared with 16% in those which did not show low E-cadherin expression and presence of Delta Np73L. Conclusion. This study shows that low E-cadherin expression is useful for predicting lymph node metastases in cases of OSCC. The predictive value is enhanced when low E-cadherin positivity is associated with Delta Np63 and Delta Np73L expression. (C)2008 Wiley Periodicals, Inc. Head Neck 30: 1475-1482. 2008