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Occupational exposure to volatile organic compounds (VOCs) may cause hematopoietic malignancy, either by single exposure to benzene or possibly due to a concomitant exposure to several VOCs. Since oxidative stress, inflammation and DNA repair pathways are closely involved in cancer development, the effect of VOC exposure on expression of proteins involved in these pathways has been studied, but epigenetic changes have not been well described. Here, DNA methylation status following occupational exposure to a VOC mixture was assessed by bisulfite sequencing of the promoter regions of seven genes involved in the mentioned pathways. Peripheral blood samples and individual-level VOC exposure data were obtained from healthy leather shoe factory workers (LS, n = 40) and gas station attendants (GS, n = 36), as well as a reference group of university employees (C, n = 66). Exposure levels for acetone, ethylbenzene, methyl ethyl ketone, n-hexane, toluene and xylene were higher in LS (p < 0.001); benzene and methyl acetate levels were higher in GS (p < 0.001). TOP2A, SOD1, and TNF-α promoter methylation status was increased in LS (p < 0.05). In LS, we also found significant correlations between GSTP1 promoter methylation and both iNOS (r = 0.37, p = 0.008) and COX-2 (r = − 0.38, p = 0.007) methylation. In exposed groups, ethylbenzene exposure levels showed a significant correlation with TOP2A methylation (β = 0.33). Our results show early, toxic effects at the epigenetic level caused by occupational exposure to high levels of a VOC mixture. These subcellular modifications may represent the initial mechanism of toxicity leading to hematopoietic malignancy, possibly due to a synergistic, hematotoxic effect of VOC mixtures.We analyzed promoter methylation in 7 genes from Mexican workers exposed to solvents.Workers from a shoe factory (LS) were exposed to the highest levels of ethylbenzene.SOD1, TNF-α and TOP2A methylation levels were higher in LS compared to controls.Ethylbenzene levels showed a positive correlation with TOP2A methylation status in LS.Epigenetic changes represent early, toxic mechanisms in VOC-induced cancer.