Recent scientific investigation has supported the important role of probiotics as a part of healthy diet for human as well as animals and may be an avenue to provide a safe, cost effective, and natural approach that adds a barrier against microbial infection. The immunomodulatory property of probiotics is the main base of designing clinical studies in various diseased conditions. Diarrhea is one of the most common symptoms in patients with HIV infection and the risk of diarrhea is increased with advanced immunodeficiency and in patients taking antiretroviral therapy. Probiotic supplements proved to be effective in shortening the duration of diarrhea and to enhance humoral responses in children and adults too. Furthermore, it is suggested that genetically bioengineered lactobacilli can significantly decrease the infectivity of HIV. Current clinical studies suggest that expanding the use of probiotics in immunocompromised patients appears promising; however, it is difficult to extrapolate results from these studies to the expected effects on human health due to very limited testing on immune function effects in humans.