IL-10, originally called cytokine synthesis inhibitory factor (CSIF), is a cytokine produced by Th2 cells that suppresses IFN-γ production by Th1 cells. It is one of the few lymphocyte suppressor factors that have been purified and cloned. IL-10 inhibits Th1 cell function only in the presence of accessory cells, especially macrophages (mφ), suggesting it may act on mφ to alter the balance between their lymphocyte-stimulating and inhibiting secretory products. IL-10 was found to be a potent suppressor of mφ TNF-α release, with an IC50 of 0.04 ± 0.03 U/ml. At 10 U/ml, IL-10 significantly suppressed mφ release of reactive oxygen intermediates (ROI), but only weakly inhibited reactive nitrogen intermediates (RNI). Since TNF-α is a T cell growth and differentiation factor, whereas ROI and RNI inhibit lymphocyte function, mφ exposed to low concentrations of IL-10 may suppress lymphocytes. mφ deactivated by higher concentrations of IL-10 may be permissive for microbial pathogens and tumor cells, as TNF-α, ROI, and RNI are major antimicrobial and tumoricidal products of mφ. IL-10's effects on mφ overlap with but are distinct from those of transforming growth factor β (TGF-β) and macrophage deactivation factor (MDF). All three mφ suppressor factors appear to act independently. IL-10 was shown to suppress mφ TNF-α release, ROI release, and RNI release, but its effects on RNI release were weaker compared to TGF-β and MDF. IL-10's actions on mφ were selective and nontoxic, with no effect on mφ adhesion, protein synthesis, or major protein synthesis. IL-10, TGF-β, and MDF appeared to act independently, as neutralizing antibodies against one did not affect the actions of the others. MDF and IL-10 differ in their molecular weight, acid stability, and effects on lymphocyte proliferation. IL-10 may suppress the antimicrobial and tumoricidal function of mφ in two ways: indirectly by inhibiting IFN-γ production by Th1 cells, which impairs mφ activation, and directly by deactivating mφ even in the presence of IFN-γ. This study demonstrates that IL-10 is a new mφ deactivation factor, distinct from TGF-β and MDF.IL-10, originally called cytokine synthesis inhibitory factor (CSIF), is a cytokine produced by Th2 cells that suppresses IFN-γ production by Th1 cells. It is one of the few lymphocyte suppressor factors that have been purified and cloned. IL-10 inhibits Th1 cell function only in the presence of accessory cells, especially macrophages (mφ), suggesting it may act on mφ to alter the balance between their lymphocyte-stimulating and inhibiting secretory products. IL-10 was found to be a potent suppressor of mφ TNF-α release, with an IC50 of 0.04 ± 0.03 U/ml. At 10 U/ml, IL-10 significantly suppressed mφ release of reactive oxygen intermediates (ROI), but only weakly inhibited reactive nitrogen intermediates (RNI). Since TNF-α is a T cell growth and differentiation factor, whereas ROI and RNI inhibit lymphocyte function, mφ exposed to low concentrations of IL-10 may suppress lymphocytes. mφ deactivated by higher concentrations of IL-10 may be permissive for microbial pathogens and tumor cells, as TNF-α, ROI, and RNI are major antimicrobial and tumoricidal products of mφ. IL-10's effects on mφ overlap with but are distinct from those of transforming growth factor β (TGF-β) and macrophage deactivation factor (MDF). All three mφ suppressor factors appear to act independently. IL-10 was shown to suppress mφ TNF-α release, ROI release, and RNI release, but its effects on RNI release were weaker compared to TGF-β and MDF. IL-10's actions on mφ were selective and nontoxic, with no effect on mφ adhesion, protein synthesis, or major protein synthesis. IL-10, TGF-β, and MDF appeared to act independently, as neutralizing antibodies against one did not affect the actions of the others. MDF and IL-10 differ in their molecular weight, acid stability, and effects on lymphocyte proliferation. IL-10 may suppress the antimicrobial and tumoricidal function of mφ in two ways: indirectly by inhibiting IFN-γ production by Th1 cells, which impairs mφ activation, and directly by deactivating mφ even in the presence of IFN-γ. This study demonstrates that IL-10 is a new mφ deactivation factor, distinct from TGF-β and MDF.