Abstract Interleukin-6 (IL-6) drives metabolic and inflammatory processes central to disease. Current knowledge implicates epigenetic mechanisms in the regulation of these pathways, including through the methylation of CpG sites. This blood-based meta-analysis of three cohorts (n = 4,361) identifies 401 IL-6–associated CpGs enriched in regulatory regions and linked to key immunometabolic genes, including AIM2, MTOR, and IL6R.