The primary interleukin-4 (IL-4) receptor complex on monocytes (type I IL-4 receptor) includes the 140-kDa α chain (IL-4Rα) and the IL-2 receptor γ chain, γ(c), which heterodimerize for intracellular signaling, resulting in suppression of lipopolysaccharide (LPS)-inducible inflammatory mediator production. The activity of IL-13 on human monocytes is very similar to that of IL-4 because the predominant signaling chain (IL-4Rα) is common to both receptors. In fact, IL-4Rα with IL-13Rα1 is designated both as an IL-13 receptor and the type II IL-4 receptor. When the anti-inflammatory activities of IL-4 and IL-13 were investigated on synovial fluid macrophages and compared with the responses by monocytes isolated from the patients at the same time as joint drainage, the response profiles differed with some responses similar in the two cell populations, others reduced on the inflammatory cells. Similar differences were recorded in the response profiles to IL-4 and IL-13 by monocytes and monocytes cultured for 7 days in macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF) (monocyte-derived macrophages, MDMac). MDMac have reduced γ(c) mRNA levels and reduced expression of the functional 64-kDa γ(c). There was a similar loss of IL-13Rα1 mRNA on monocyte differentiation. In turn, there was a significant reduction in the ability of IL-4 and IL-13 to activate STAT6. These findings suggest that different functional responses to IL-4 and IL-13 by human monocytes and macrophages may result from reduced expression of γ(c) and IL-13Rα1.