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Background: Ambient air pollution mixtures including fine particulates and gases have been associated with cardiovascular disease (CVD). Although mechanisms underlying the associations remain largely uncharacterized to date, examining epigenetic responses to air pollution mixtures may identify biological systems affected by exposure and provide insight into the pathophysiology and environmental epidemiology of CVD. Therefore, we undertook a multi-pollutant, methylome-wide study of associations between DNA methylation (DNAm) at 485,000 Cytosine-phosphate-Guanine (CpG) sites and pollutants regulated by the U.S. Environmental Protection Agency under the Clean Air Act.Methods: Data from the Atherosclerosis Risk in Communities Study and three sub-studies within the Women’s Health Initiative (WHI) included information on 8,567 participants, 83% of whom were women, 46% African American, and 9% Hispanic/Latino (mean age, 61.3 years). Daily mean, geocoded participant address-specific concentrations of ambient particulate matter with diameter ≤ 10μm (PM10), ≤2.5μm (PM2.5), and 2.5-10μm (PM2.5-10); ozone (O3); nitrogen dioxide (NO2); nitrogen oxides (NOx); carbon monoxide (CO); and sulfur dioxide (SO2) were averaged over 2, 7, 28, and 365 days before measurement of leukocyte DNAm in whole blood. Methylome-wide, pollutant-DNAm associations were estimated separately at each averaging period in each stratum defined by race/ethnicity and study using multi-level, linear mixed models adjusting for socio-demographic, behavioral, and meteorological characteristics; estimated leukocyte proportions; and technical covariates. Estimates were combined across strata in pollutant- and period-specific, fixed-effects, inverse-variance weighted meta-analyses. Then multi-pollutant, period-specific effects were examined using the adaptive sum of powered scores (U) test (aSPU). CpG sites associated with multi-pollutant significance (aSPU P < 1.0 x 10-7) were characterized in silico to assess their putative function and biological plausibility.Results: Overall analyses identified a significant, 28-day mean, multi-pollutant association at cg15008743 near ZNF83 on chromosome 19 (p = 1x10-7) and a highly-suggestive 28-day mean, multipollutant association at cg00489219 near ZNF621 on chromosome 3 (p = 5x10-7). ZNF83 and ZNF621 encode zinc finger proteins with a potentially broad reach across biological systems given their transcription factor, metal, and DNA binding activities. ZNF621 also harbors rare genetic variants with large effects on blood pressure.Discussion: Methylome-wide associations of DNAm with EPA-regulated ambient air pollutants suggest biologically plausible pathways underpinning the increasingly well-documented ties between multi-pollutant mixtures and cardiovascular disease.