Genetic predisposition, environmental factors, and infectious agents interact in the development of gastric diseases.Helicobacter pylori(Hp) and Epstein–Barr virus (EBV) infection has recently been shown to be correlated with these diseases. A cross-sectional study was performed on 100 hospitalized Italian patients with and without gastric diseases. The patients were stratified into four groups. Significant methylation status differences among CDH1, DAPK, COX2, hMLH1 and CDKN2A were observed for coinfected (Hp-EBV group) patients; particularly, a significant presence of COX2 (p= 0.0179) was observed. For microsatellite instability, minor stability was described in the Hp-HBV group (69.23%,p= 0.0456). Finally, forp53 mutationin the EBV group, exon 6 was, significantly, most frequent in comparison to others (p= 0.0124), and in the Hp-EBV group exon 8 was, significantly, most frequent in comparison to others (p< 0.0001). A significant positive relationship was found between patients with infection (Hp, EBV or both) andp53 mutation(rho = 0.383,p= 0.0001), methylation status (rho = 0.432,p< 0.0001) and microsatellite instability (rho = 0.285,p= 0.004). Finally, we observed among infection and methylation status, microsatellite instability, andp53 mutationa significant positive relationship only between infection and methylation status (OR = 3.78,p= 0.0075) and infection andp53 mutation(OR = 6.21,p= 0.0082). According to our analysis, gastric disease in the Sicilian population has different pathways depending on the presence of various factors, including infectious agents such as Hp and EBV and genetic factors of the subject.