Purpose: Metabolic syndrome (MetS) is a complex, multifactorial, systemic disease characterized by the coexistence of metabolic abnormalities and is clinically defined by the presence of at least three important risk factors: excess abdominal fat, a low serum concentration of high-density lipoprotein cholesterol, high serum triglyceride levels, high blood pressure, and high serum glucose levels. Understanding the role of epigenetics in MetS remains challenging because of the complexity of its multifactorial mechanisms. Thus, this study aimed to evaluate the factors associated with MetS and their association with methylation in the Methods: This cross-sectional study included 353 volunteers who were patients of the primary care service of the Brazilian Public Health System. Socioeconomic status, lifestyle, and health conditions were assessed, along with anthropometric measurements, blood pressure readings, and the collection of blood samples for biochemical and molecular analyses. The methylation levels of the promoter region (1F) of the Results: The prevalence of MetS was 40.5% in the present study, and factors associated with MetS in the multivariate Poisson regression were age, excess body fat, serum v Conclusion: In summary, these findings demonstrate a site-specific association between NR3C1 DNA methylation and MetS and highlight a molecular profile that coexists with established clinical risk factors. These results suggest a potential epigenetic role of the NR3C1 gene in MetS, contributing to a better understanding of its etiology.