We performed methylation specific PCR to explore the mechanism of inactivation of tumor suppressor genes P15, P16, P53 and VHL in 48 oral SCC. The frequencies of aberrant methylation on the promoter of the P15, the P16, the P53 and the VHL genes were 0.27 (13/48), 0.42 (20/48), 0.04 (2/48) and none, respectively. Altogether, over 50% of the samples showed the CpG-island methylation modification in at least one of the three tumor suppressor genes, indicating that the frequent inactivation of these genes may be an important step during oral cancer development, and the methylation inactivation of P15 or P16 may occur at pre-cancerous stage.