Some causal bases of stroke remain unclear, but the nutritional effects on the epigenetic regulation of different genes may be involved. The aim was to assess the impact of epigenetic processes of human tumor necrosis factor (TNF-alpha) and paraoxonase (PON) promoters in the susceptibility to stroke when considering body composition and dietary intake. Twenty-four patients (12 non-stroke/12 stroke) were matched by sex (12 male/12 female), age (mean 7012years old), and BMI (12 normal-weight/12 obese; mean 28.16.7kg/m(2)). Blood cell DNA was isolated and DNA methylation levels of TNF-alpha (-186 to +349bp) and PON (-231 to +250bp) promoters were analyzed by the Sequenom EpiTYPER approach. Histone modifications (H3K9ac and H3K4me3) were analyzed also by chromatin immunoprecipitation in a region of TNF-alpha (-297 to -185). Total TNF-alpha promoter methylation was lower in stroke patients (p<0.001) and showed no interaction with body composition (p=0.807). TNF-alpha and PON total methylation levels correlated each other (r=0.44; p=0.031), especially in stroke patients (r=0.72; p=0.008). The +309 CpG methylation site from TNF-alpha promoter was related to body weight (p=0.027) and the region containing three CpGs (from -170 to -162bp) to the percentage of lipid intake and dietary indexes (p<0.05) in non-stroke patients. The methylation of PON +15 and +241 CpGs was related to body weight (p=0.021), waist circumference (p=0.020), and energy intake (p=0.018), whereas +214 was associated to the quality of the diet (p<0.05) in non-stroke patients. When comparing stroke vs non-stroke patients regarding the histone modifications analyzed at TNF-alpha promoter, no changes were found, although a significant association was identified between circulating TNF-alpha level and H3K9ac with H3K4me3. TNF-alpha and PON promoter methylation levels could be involved in the susceptibility to stroke and obesity outcome, respectively. The dietary intake and body composition may influence this epigenetic regulation in non-stroke patients.