Objective To investigate the tumor suppressor genes of phlegm DNA in smokers, and analyze the correlation between methylation level of tumor suppressor gene promoter and chronic mucus hypersecretion (CMH). Methods The study recruited the patients who were admitted in the respiratory department during 2013-2016 in this hospital, including 700 cases of urban smokers and 380 cases of rural smokers. Eleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used in the sputum sample of 700 individuals in the urban smokers cohort. Replication was performed in 380 individuals from the rural smokers cohort. Results CMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the urban and rural groups (OR=2.73, 95%CI 1.53-4.93, P=0.001; OR=2.96, 95%CI 1.47-5.94, P=0.002, respectively). Furthermore, the association between methylation and CMH was more obvious among 139 male former smokers with persistent CMH compared with current smokers (SULF2, OR=3.64, 95%CI 1.57-8.35, P=0.002). Conclusion These findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer.