Aim Our goal was to investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. Materials and Methods For this analysis, we included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at visit 4 and had available data on DNA methylation. DNA methylation levels were compared by periodontal disease severity and edentulism to identify differentially methylated regions (DMRs) and evaluate the CpGs belonging to those DMRs using multinominal logistic regression. Results We identified a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared to no/mild periodontal disease in European American participants. A separate region in an unknown gene (located in Chr10: 743,992-744,958) demonstrated significant positive association with edentulism compared to no/mild periodontal disease in African American participants. Four CpGs in a region located within HOXA4 were significantly hypermethylated in severe periodontal disease compared to no/mild periodontal disease in African American participants. Conclusions Our study highlights epigenetic variations in ZPF57 and HOXA4 that were significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci. Keywords: Periodontitis, periodontal disease, DNA methylation, Illumina Infinium HumanMethylation450K, epigenome-wide association study (EWAS), peripheral blood.