Objective To investigate the relationship between detection of promoters methylation status of cancer suppressor genes such as the cell-cycle inhibitor gene CDKN2A (p16),fragile histidine triad (FHIT) genes in peripheral blood and the development of lung cancer.Methods Real-time quantitative methylation specific PCR was used to detect the status of p16 and FHIT gene promoters methylation in peripheral blood collected from 180 lung cancer patients and 180 normal controls.The differences between lung cancer group and control group in methylation status were analyzed and compared.The effect of age,gender,smoking,histological type and clinical stage on the methylation of the referred two gene promoters were discussed,and the relationship between lung cancer and risk factors,such as age,gender,smoking and methylation level of the referred gene promoters was studied.Results There were statistically significant differences in methylation levels between p16 and FHIT genes (p16:Z =-2.560,P =0.010;FHIT:Z =-2.797,P =0.005).These two genes were more highly methylated in lung cancer group compared with control group.The methylation levels of p16 and FHIT genes had no obvious relevance with gender,age,smoking history,histological type and clinical stage (p16:Z =-1.121,P=0.262,Z=-0.304,P =0.761,Z =-0.082,P=0.935,x2=0.582,P=0.748,Z=-1.605,P=0.108;FHIT:Z =-0.169,P =0.886,Z =-0.411,P =0.681,Z =-1.095,P =0.273,x2 =2.97,P =0.227,Z =-1.189,P =0.234).Single-factor non-conditional logistic regression analysis showed that gender had no risk impact on lung cancer (OR =1.274,P =0.297),while age,smoking and methylation levels of p16 and FHIT genes promoted the development of lung cancer (OR =1.952,1.888,1.598,1.830,P =0.002,0.003,0.027,0.005,respectively).Multiple-factor nonconditional logistic regression analysis showed that the risk of lung cancer increased with methylation status of FHIT gene (OR =1.867,P =0.006),and the risk of lung cancer was possibly increased while the methylation level of p16 gene increased (OR =1.477,P =0.086).Measuring the methylation levels of two genes jointly was more valuable (AUC=0.832,P ＜0.01).Conclusions The methylation levels of p16 and FHIT gene promoters in peripheral blood have relationship with lung cancer.The combined detection of two genes is more valuable than single gene detection for diagnosis of lung cancer.Detecting the methylation levels of p16 and FHIT gene promoters may become a new method in early diagnosis and screening of lung cancer.