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Little is known about the potential role of epigenetic marks as predictors of the resolution of obesity-related comorbidities after bariatric surgery. In this study, 20 patients were classified according to the metabolic improvement observed 6 months after sleeve gastrectomy, based on the diagnosis of metabolic syndrome, into responders if metabolic syndrome reversed after bariatric surgery (<i>n</i> = 10) and non-responders if they had metabolic syndrome bariatric surgery (<i>n</i> = 10). Blood DNA methylation was analyzed at both study points using the Infinium Methylation EPIC Bead Chip array-based platform. Twenty-six CpG sites and their annotated genes, which were previously described to be associated with metabolic status, were evaluated. Cg11445109 and cg19469447 (annotated to Cytochrome P450 2E1 (<i>CYP2E1</i>) gene) were significantly more hypomethylated in the responder group than in the non-responder group at both study points, whilst cg25828445 (annotated to Nucleolar Protein Interacting With The FHA Domain Of MKI67 Pseudogene 3 (<i>NIFKP3</i>) gene) showed to be significantly more hypermethylated in the non-responder group compared to the responder group at both study points. The analysis of the methylation sites annotated to the associated genes showed that <i>CYP2E1</i> had 40% of the differentially methylated CpG sites, followed by Major Histocompatibility Complex, Class II, DR Beta 1 (<i>HLA-DRB1</i>) (33.33%) and Zinc Finger Protein, FOG Family Member 2 (<i>ZFPM2</i>) (26.83%). Cg11445109, cg19469447 and cg25828445 could have a role in the prediction of metabolic status and potential value as biomarkers of response to bariatric surgery.