Many chronic human immunodeficiency virus (HIV) patients suffer from gastric complaints, including gastric tuberculosis and coinfection of other pathogens. Recent work has demonstrated that a variety of nonimmune cells can act as viral reservoirs, even at the early stage of HIV infection. In this study, we detect HIV viral particles, proteins, and nucleic acids in gastric epithelial cells using clinical samples. These observations are further supported by a simian immunodeficiency virus-infected macaque model. Further, the number of HIV-infected gastric epithelial cells is positively associated with blood viral load, and is negatively correlated with CD4 lymphocyte cell counts. We also demonstrate that HIV infection is accompanied by severe inflammatory response in gastric mucosa. Additionally, HIV infection activates signal transducer and activator of transcription 3 and RelA, and enhances the production of interleukin 6 and tumor necrosis factor alpha in gastric epithelial cells. The present data suggest that the gastric epithelial cells are natural targets of HIV infection, and HIV infection in epithelial cells contributes to HIV-induced gastric mucosal inflammation.