Chronic immune activation and systemic inflammation are underlying causes of acquired immunodeficiencysyndrome (AIDS). Products of virus replication and microbial translocation, co-infection or opportunistic pa-thogens, and danger-associated molecular patterns have been reported to contribute to chronic immune acti-vation and inflammation in human immunodeficiency virus type-1/simian immunodeficiency virus (HIV-1/SIV)infection or other disease. To develop new strategies and therapies for HIV-1/AIDS, we tested if the CD24 and Fcfusion protein (CD24Fc), which interacts with danger-associated molecular patterns and sialic acid binding Ig-like lectin to attenuate inflammation, can protect Chinese rhesus macaques (ChRMs) with SIV infection. Wefound that CD24Fc treatment decreased weight loss, wasting syndrome, intractable diarrhea, and AIDS mor-bidity and mortality, while it was well tolerated by SIV-infected animals. Corresponding to the elimination ofintractable diarrhea, CD24Fc significantly reduced the expression of IL-6 and indoleamine 2, 3-dioxygenase-1 inperipheral blood mononuclear cell and inflammation in the ileum, colon and rectum based on the reduction ofinflammatory cells, pathological scores and expression of inflammatory cytokines. Furthermore, althoughCD24Fc did not restore CD4 + T cell number or significantly change T cell subsets or CD4 + T cell activation, itmaintained low levels of plasma soluble CD14, CD8 + T cell activation, viral load and proviral load in theperipheral blood mononuclear cells and marrow. These results suggested that CD24Fc confers protection to SIV-infected ChRMs against progression to AIDS. It was also implied that CD24Fc may be a potential therapeuticapproach for the control of HIV-1/AIDS.