Interaction of HIV with cultured human monocytes triggers not only cytokine production but also the release of natural cytokine inhibitors such as the soluble TNF receptors, levels of which are increased in the circulation of HIV-infected patients. We found that HIV-1 LAI induced the production by human monocytes from HIV-seronegative donors of another type cytokine inhibitor, the IL-1Ra receptor antagonist (IL-1Ra). HIV mainly induced the secreted form (83%) of IL-1Ra through de novo mRNA synthesis. IL-1Ra production was triggered at an early step of the infection process and involved the HIV envelope protein and the CD4 receptor. HIV-triggered IL-1Ra production occurred after a lag time, suggesting an indirect mechanism. Neutralizing Abs to IL-1 beta and IL-10 had no effect, while simultaneous treatment with anti-TNF-alpha, anti-granulocyte-macrophage CSF, and anti-TGF-beta nearly abrogated IL-1Ra release, supporting an indirect induction through the concerted action of the co-produced cytokines. IL-1Ra was induced by HIV in a mean 1,000-fold increase over IL-1 alpha beta, a ratio 20-fold higher than that obtained with LPS. This production masked 80% of IL-1 bioactivity in HIV-induced monocyte supernatants. These results suggest that the net balance between pro-inflammatory cytokines and their natural inhibitors could be critical in the control of the inflammatory process associated with HIV infection.