Death-associated protein-kinase (DAP-Kinase) is a serine/threonine kinase with a death domain that is involved in apoptosis induced by interferon-g, TNF-a, and Fas ligand. Epigenetic down-regulation of DAP-Kinase gene expression by hypermethylation of its promoter region was reported in B-cell malignancies. Previous pathoepidemiologic studies indicated that thyroid lymphoma (TL) evolves among active lymphoid cells in chronic lymphocytic thyroiditis (CLTH). With use of methylation-specific polymerase chain reaction, the methylation status of DAP-Kinase CpG island was examined in thyroid lesions of 19 cases with TL and 9 with CLTH. The frequency of methylation was higher in TL cases (16 of 19, 84.2%) than in CLTH cases (2 of 9, 22.2%) (p < 0.01). DNA extracted from peripheral blood leukocytes from TL and CLTH cases never showed methylation, indicating that the methylation occurred somatically in the lesional lymphocytes in thyroid. These findings suggested that methylation of the DAP-Kinase promoter region might be involved in the development of TL from CLTH.