Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral cavity. Human cancers are characterized by an imbalance of regulatory mechanisms controlling different cellular pathways, including apoptosis. Apoptosis occurs in a wide variety of physiological processes, such as embryonic development, tissue homeostasis or immune defense, and its role is to remove harmful, damaged, or unwanted cells. Defective apoptosis represents an important causative factor in the development/progression of cancer, and the ability of tumor cells to evade apoptosis can play a significant role in their resistance to conventional anticancer treatment. We investigated the expression profile of genes involved in the apoptotic mechanism in 21 paired tissue samples (OSCC and adjacent normal oral mucosa) by cDNA macroarray, in order to identify differentially expressed genes in oral cancer compared to normal tissue. To validate the results obtained by cDNA macroarray, quantitative real-time PCR, Western blot, and immunohistochemical analyses were performed. Results obtained by cDNA macroarray analysis showed different expression levels of CRADD, FADD, ATM, APAF1, and TP63 genes in OSCC compared to normal mucosa. Differential gene expression measurements (tumor vs. normal tissue) performed by real-time PCR showed an overexpression of FADD and a downregulation of ATM. Moreover, Western blot analysis confirmed that both CRADD and APAF-1 were decreased in OSCC compared to normal oral mucosa. As showed by immunohistochemistry, OSCC exhibited increased expression of p63 compared to normal tissue. Interestingly, a statistically significant positive correlation was found between p63 expression and the histological grade. © 2012 Wiley Periodicals, Inc.