Fish oil is a natural product that has shown efficacy for managing inflammatory conditions with few side effects. There is emerging evidence that crosstalks between gut epithelial cells and immune cells contribute to chronic infectious diseases. HIV-infected (HIV+) older adults show age-related co-morbidities at a younger age than their uninfected counterparts. Persistent inflammation related to the chronic viral infection and its sequelae is thought to contribute to this disparity. However, little is known about whether fish oil reduces intestinal inflammation in HIV + patients. We measure inflammation and gut barrier function in HIV + older adults (median age = 52, N = 33), following 12 weeks of fish oil supplementation (a total daily dose of 1.6 g of omega-3 fatty acids). We showed a reduction in inflammation and gut permeability as measured by CD14, inflammatory cytokines, lipopolysaccharide, and lipopolysaccharide binding protein. The results indicate that older HIV + adults may benefit from a diet supplemented with the omega-3 fatty acids found in fish oil.