Background/purpose: Oral squamous cell carcinoma (OSCC) is the fourth major cause of mortality among males in Asia. The tumorigenesis of OSCC is a multi-step process characterized by sequential morphological changes. The extent of lymph node metastasis is a major determinant in the prognosis of cancer. Hypermethylation is an important pathway for repression of gene transcription in cancer cells and a promising marker for cancer detection. It is also found in early metastatic cancer patients. Materials and methods: Sixty-four histologically confirmed OSCC tissues and corresponding nontumorous tissues were enrolled in this study. DNA was extracted. The promoter methylation status of the p16, death-associated protein kinase (DAPK), MGMT, and glutathione S-transferase genes in OSCC tissues was evaluated by a methylation-specific polymerase chain reaction analysis. Results: Frequencies of promoter hypermethylation of p16, DAPK, and MGMT in OSCC tissue were 67.2%, 45.3%, and 31.3%, respectively. No methylation was found in normal oral mucosa. Methylation rates of MGMT (50%) and DAPK (55.6%) in metastasized OSCC were higher than those of MGMT (23.9%) and DAPK (41.3%) in nonmetastasized OSCC. No glutathione S-transferase P methylation was found in any tissue samples. Conclusions: Our study supports the hypothesis that hypermethylation of p16 gene promoters may indicate a high risk of oral cancer, and hypermethylation of the MGMT and DAPK genes may be a major indicator of early OSCC metastasis.