BACKGROUND/OBJECTIVES: This study investigated variations in DNA methylation patterns associated with chronic pain and propensity for recurrent pressure injuries (PrI) in persons with spinal cord injury (SCI). METHODS: Whole blood was collected from 81 individuals with SCI. DNA methylation was quantified using Illumina genome-wide arrays (EPIC and EPICv2). Comprehensive clinical profiles collected included secondary health complications, in particular current PrI and chronic pain. Relationships between recurrent PrI and chronic pain and whether the co-occurrence of both traits was mediated by changes in DNA methylation were investigated using R packages limma, DMRcate and mCSEA. RESULTS: Three differentially methylated positions (DMPs) (cg09867095, cg26559694, cg24890286) and one region in the micro-imprinted locus for are associated with chronic pain in persons with SCI. The study cohort was stratified by PrI status to identify any sites associated with chronic pain and while the same three sites and region were replicated in the group with no recurrent PrI, two novel, hypermethylated (cg21756558, cg26217441) sites and one region in the protein-coding gene were identified in the group with recurrent PrI. Gene enrichment and genes associated with specific promoters using MetaScape identified several shared disorders and ontology terms between independent phenotypes of pain and recurrent PrI and interactive sub-groups. CONCLUSIONS: DMR analysis using mCSEA identified several shared genes, promoter-associated regions and CGI associated with overall pain and PrI history, as well as sub-groups based on recurrent PrI history. These findings suggest that a much larger gene regulatory network is associated with each phenotype. These findings require further validation.