Interleukin-4 (IL-4) has potent anti-inflammatory properties on monocytes and suppresses lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) and IL-1β production. Culture with interferon (IFN-γ) alters human monocyte responses to IL-4 by multiple mechanisms. As previously published, IFN-γ reduced IL-4-activated signal transducer and activator of transcription-6 (STAT-6). This correlated with an inability of IL-4 to suppress LPS-induced TNF-α but not IL-1β production. A second mechanism, apparent some 48 h after exposure to IFN-γ, involved a significant suppression of IL-4 receptor (IL-4R) expression at the cell surface, and this correlated with the loss of additional functional responses to IL-4, including IL-4-induced suppression of LPS-induced IL-1β production. This study identified a further role of IFN-γ on IL-4 responses, including reduced IL-4R surface expression by human monocytes. Increased release of soluble γc from IFN-γ-treated monocytes provides an additional mechanism by which IFN-γ may control the functional activity of IL-4. This study characterizes further the opposing effects of the type 1 and type 2 cytokine regulatory systems.