Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemiawith potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most ofthe previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemiatypes. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation usingmethylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) andDAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15(45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlightedan essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases,whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genesper patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16).Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03)indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycleand apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumorspecific inactivation of the cell cycle and apoptotic pathways.