To examine the mechanism of hexavalent chromium [Cr(VI)]-induced carcinogenesis, a cross-sectional study in workers with or without exposure to Cr(VI) as well as in vitro administration of Cr(VI) in 16HBE cells was conducted. We explored the associations between Cr(Vl) exposure, methylation modification of DNA repair genes and their expression levels, and genetic damage. Results showed that hypermethylation of CpG sites were observed in both occupationally exposed workers and 16HBE cells administrated Cr(VI). DNA damage markers including 8-hydroxydeoxyguanosine (8-OHdG) and micronucleus frequency in Cr(VI)-exposed workers were significantly higher than the control group. Among workers, blood Cr concentration was positively correlaed with the methylation level of CpG sites in DNA repair genes including CpG6,7, CpG8, CpG9,10,11 of MGMT, CpG11 of HOGG1; CpG15,16,17, CpG19 of RAD51, and genetic damage markers including 8-OHdG and micronucleus frequency. Significant negative association between methylation levels of CpG sites in DNA repair genes and corresponding mRNA was also observed in 16HBE cells. This indicated that Cr(VI) exposure can down-regulate DNA repair gene expression by hypermethylation, which leads to enhanced genetic damage. The methylation level of these CpG sites of DNA repair genes can be potential epigenetic markers for Cr(VI)-induced DNA damage. (C) 2018 Elsevier Ltd. All rights reserved.