Severe acne is a chronic inflammatory skin condition that is affected by both genetic and environmental factors. DNA methylation is associated with a variety of inflammatory skin diseases, but its role in severe acne is unclear. In this study, we conducted a two-stage epigenome correlation study using 88 blood samples to identify disease-related differential methylation sites. We found close associations between the DNA methylation at 23 differentially methylated sites (DMSs) and severe acne, including PDGFD, ARHGEF10 , etc. Further analysis revealed that differentially methylated genes ( PARP8 and MAPKAPK2 ) were also expressed differently between severe acne and health control groups. These findings lead us to speculation that epigenetic mechanisms may play an important role in the pathogenesis of severe acne.