Background and aims: Metabolic-dysfunction associated steatotic liver disease (MASLD) is highly prevalent in individuals with type 2 diabetes mellitus (T2DM), contributing to diabetes complications and cardiovascular disease (CVD). Epigenetic changes, including DNA methylation, may influence disease susceptibility and progression. This study aimed to investigate global and site-specific methylation patterns in T2DM individuals with MASLD-related liver fibrosis and their correlation with candidate gene expression. Materials and methods: Global demethylation intermediates (5-hydroxymethylcytosine [5hmC], 5-formylcytosine [5fC]), and poly (ADP-ribose); (PAR) were measured in peripheral blood cells (PBMC) using ELISA. Site-specific DNA methylation profiling of candidate genes associated with inflammation, glucose and lipid metabolism (SOCS3, SREBF1, and TXNIP) was performed using mass spectrometry-based bisulfite sequencing. Expression levels of SOCS3, CD68, IL-6, and MCP-1 mRNA were assessed via real-time PCR. Liver fibrosis was estimated by calculating the validated Fibrotic NASH Index (FNI) score. Results: T2DM patients at moderate-high fibrosis risk (FNI ≥0.33) had greater global levels of demethylation intermediates and lower methylation levels of specific CpG sites in SOCS3 gene compared to T2DM subjects with lower hepatic fibrosis risk (all p<0.05). FNI positively correlated with global level of demethylation intermediates (5hmC: r=0.72, p<0.001; 5fC: r=0.57, p=0.006) and inversely correlated with methylation levels of several CpG sites in the SOCS3 gene locus (all p<0.05). Furthermore, FNI linearly associated with PAR level (r=0.63, p<0.001) and with SOCS3 (r=0.36, p=0.032), IL-6 (r=0.49, p=0.007) and MCP1 (r=0.58, p<0.001) mRNA levels. Conclusion: T2DM patients with estimated MASLD-related liver fibrosis exhibit differential methylation patterns in PBMC both at global levels and in the candidate gene SOCS3, which is associated with inflammation and fibrosis development. These epigenetic changes may serve as potential biomarkers for MASLD progression and contribute to understanding the increased cardiovascular risk in individuals with concurrent T2DM and MASLD, especially in presence of more pronounced liver fibrosis.