Tobacco use and e-cigarette use both induce shared DNA methylation (DNAme) changes linked to carcinogenesis. This study analyzed DNAme patterns in over 3,500 buccal/saliva, cervical, and blood samples from individuals exposed to tobacco or e-cigarettes, revealing 535 smoking-related DNAme loci clustered into four functional groups, including detoxification and growth signaling. These loci showed hypermethylation in buccal epithelial cells of smokers and were associated with lung cancer development. Similarly, these CpGs were hypermethylated in e-cigarette users with limited smoking histories, suggesting a potential role in carcinogenesis. The study highlights cell-type-specific epigenetic changes induced by smoking-related products, with implications for cancer risk. DNAme analysis in epithelial and immune cells revealed distinct patterns, with epithelial hypoM and hyperM CpGs associated with cancer progression. E-cigarette users exhibited similar epigenetic changes to smokers, with proximal epithelial hyperM showing significant hypermethylation. Smoking-related methylation changes were also linked to cervical cancer and CIS progression. The study suggests that DNAme patterns in buccal and blood samples could predict lung cancer risk in smokers, emphasizing the need for further research into the molecular and health impacts of e-cigarettes.Tobacco use and e-cigarette use both induce shared DNA methylation (DNAme) changes linked to carcinogenesis. This study analyzed DNAme patterns in over 3,500 buccal/saliva, cervical, and blood samples from individuals exposed to tobacco or e-cigarettes, revealing 535 smoking-related DNAme loci clustered into four functional groups, including detoxification and growth signaling. These loci showed hypermethylation in buccal epithelial cells of smokers and were associated with lung cancer development. Similarly, these CpGs were hypermethylated in e-cigarette users with limited smoking histories, suggesting a potential role in carcinogenesis. The study highlights cell-type-specific epigenetic changes induced by smoking-related products, with implications for cancer risk. DNAme analysis in epithelial and immune cells revealed distinct patterns, with epithelial hypoM and hyperM CpGs associated with cancer progression. E-cigarette users exhibited similar epigenetic changes to smokers, with proximal epithelial hyperM showing significant hypermethylation. Smoking-related methylation changes were also linked to cervical cancer and CIS progression. The study suggests that DNAme patterns in buccal and blood samples could predict lung cancer risk in smokers, emphasizing the need for further research into the molecular and health impacts of e-cigarettes.