More than 80% of rhesus monkeys infected with simian immunodeficiency virus (SIV) were found to have elevated levels of soluble interleukin-2 receptor (IL-2R) in their serum during the course of infection. All long-term survivors had stably elevated levels of soluble IL-2R. The highest levels of soluble IL-2R correlated with the expression of IL-2R on tissue macrophages. Although IL-2R expression was induced on alveolar macrophages by infection with SIV in vitro, expression of IL-2R on tissue macrophages in vivo was not associated with concurrent SIV protein expression in the same cells. Moreover, in animals with high soluble IL-2R levels, there was an inverse relationship between the numbers of cells expressing IL-2R and cells expressing viral protein. The results suggest that the induction of IL-2R may be an indirect or secondary effect of SIV infection. Changes in expression of macrophage-elaborated factors, such as that of IL-2R described in this report, may play a crucial role in some of the pathologic features of acquired immunodeficiency syndrome.