Background This study analyzes genome-wide epigenome in patients with nociceptive and neuropathic chronic pain subtypes. Chronic pain itself and the transition from acute to chronic pain may be epigenetically controlled. Method The authors conducted a cross-sectional study of a genome-wide DNA methylation analysis. It was performed using the blood DNA reduced representation bisulfite sequencing technique. The prospective patients include those with chronic nociceptive pain, chronic neuropathic pain, and healthy controls. Three prospective cohorts were compared at both the single CpG and differentially methylated region levels. Key findings The study reported that chronic nociceptive pain and chronic neuropathic pain differ in their etiology. However, they have a common main symptom, pain, although it has different characteristics. Epigenetic disturbances accompanying nociceptive pain are very different from those accompanying neuropathic pain. In nociceptive pain, the epigenetic disturbance observed would affect the function of the opioid analgesic system. In neuropathic pain, it would affect that of the GABAergic reward system. Conclusion In conclusion, an epigenome-wide study identified CpGs methylation signatures in the blood, discriminating nociceptive from neuropathic types of chronic pain. Genes associated with these signatures appear to have essential functions in the neuro-musculoskeletal system. The new targets identified in our study might help to discover more specific treatments for these pains.