INTRODUCTION: The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16. Absence of expression of the p16 gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16 expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16 expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16 via methylation would correlate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC). METHODS: Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16 would have a better response and survival following DHAC treatment than their nonmethylated counterparts. RESULTS: Methylation of p16 was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant. CONCLUSIONS: There was no significant correlation between the presence of p16 methylation and response to DHAC therapy or overall survival.