Abstract: Objective To analyze the relationship between CDKN2A and CDKN2B gene methylation with aging in the general population. Methods We collected peripheral blood samples from 284 male and 246 female healthy subjects for detection of methylation levels of CDKN2A and CDKN2B genes using quantitative methylation-specific PCR (qMSP). The relationship between the methylation levels of CDKN2A and CDKN2B genes and aging was analyzed using Spearman or Pearson correlation test. Results We found a significant positive correlation between the methylation levels of the two genes in these subjects (P<0.05). In the overall population as well in the female subjects, CDKN2A methylation was found to be inversely correlated with age (P<0.05). The methylation levels of CDKN2A and CDKN2B genes were inversely correlated with TG, ApoE, Lp(a) and AST in the overall population (P<0.05). In both the female and male subjects, the methylation levels of the two genes were inversely correlated with Lp(a) (P<0.05). In the male subjects, CDKN2A methylation was inversely correlated with AST (P< 0.05), while CDKN2B methylation was inversely correlated with HDL and ApoE (P<0.05). In the female subjects, CDKN2A methylation was positively correlated with LDL and inversely correlated with ApoE and AST (P<0.05). Conclusion The methylation levels of CDKN2A and CDKN2B are closely related to age and the levels of multiple proteins in healthy subjects.