Rheumatoid arthritis (RA) is a complex chronic systematic disease with progressive destruction of the joints by invasive synoviocytes. To characterize the key regulators involved in the development of RA, we obtained multilayer epigenomics data including DNA methylation by whole-genome bisulfite sequencing, miRNA profiles, genetic variations by whole-exome sequencing, and mRNA profiles from synoviocytes of RA and osteoarthritis (OA) patients. The overall DNA methylation patterns were not much different between RA and OA, but 523 low-methylated regions (LMRs) were specific to RA. The LMRs were preferentially localized at the 5′ introns and overlapped with transcription factor binding motifs for GLI1, RUNX2, and TFAP2A/C. Single base-scale differentially methylated CpGs were linked with several networks related to wound response, tissue development, collagen fibril organization, and the TGF-β receptor signaling pathway. Further, the DNA methylation of 201 CpGs was significantly correlated with 27 expressed miRNA genes. Our interpretation of epigenomic data of the synoviocytes from RA and OA patients is an informative resource to further investigate regulatory elements and biomarkers responsible for the pathophysiology of RA and OA.