An important pathway of gene transcriptional inactivation is hypermethylation at the CpG islands of promoter regions. Some tumor suppressor genes have been reported to harbor promoter hypermethylation in head and neck cancer. We studied DNA hypermethylation of 4 genes in 42 cases of primary head and neck cancer. We applied methylation specific PCR for p16, RAR-beta, RASSF1A, and Fhit genes. Hypermethylation was detected at p16 in 43%, at RAR-beta in 40%, at RASSF1A in 12%, and at Fhit in none of the cases. Hypermethylation of at least one gene was detected in 26 (62%) of the 42 cases. No significant correlation was seen between methylation status and clinicopathological findings or prognosis. Hypermethylation of several tumor-associated genes plays an important role in tumorigenesis of head and neck cancer. We discuss clinical implications and their application.