Macrophages (Mφ) comprise a heterogeneous population of cells with various immune and homeostatic functions. Recently, we have described type-1 and type-2 human monocyte-derived Mφ subsets. Although both support outgrowth of intracellular mycobacteria, Mφ-1 secretes interleukin (IL)-23/IL-12 and supports T helper cell type 1 (Th1) responses, whereas Mφ-2 fails to produce IL-23/IL-12, predominantly secretes IL-10, and inhibits Th1 function. Here, we further describe the phenotypic and functional profiles of Mφ-1 and Mφ-2 in response to microbial antigens and interferon-γ (IFN-γ) and CD40L as costimulatory T cell back-talk signals. Activated IL-23⁺/IL-12⁺ Mφ-1 secreted IL-1β, IL-18, IL-6, and tumor necrosis factor-α (TNF-α), as well as IL-8, monocyte chemoattractant protein-1 (MCP-1), IFN-inducible protein 10 (IP-10), Mφ inflammatory protein-1β (MIP-1β), regulated on activation, normal T expressed and secreted (RANTES), Mφ-derived chemokine (MDC), and (low levels of) pulmonary and activation-regulated chemokine and thymus and activation-regulated chemokine (TARC), corroborating their proinflammatory function. Regardless of the stimulus, Mφ-2 maintained their IL-10⁺ signature cytokine profile and produced no or relatively low levels of IL-12p40, IL-1β, IL-6, TNF-α, MDC, or TARC. It is remarkable that Mφ-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1β, and RANTES, suggesting an active role for these cells in regulating cellular immunity and homeostasis. Mφ-1 and Mφ-2 expressed similar levels of Toll-like receptor and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as microbial pattern recognition receptors. Mφ-2, unlike Mφ-1 but like other nonclassical Mφ described previously, expressed CD163 and down-modulated human leukocyte antigen and costimulatory molecules specifically upon activation. These findings demonstrate how Mφ-1/Mφ-2 polarization can differentially skew the host response toward pro- or anti-inflammatory immune responses, respectively. This is likely to be relevant for host-pathogen interactions in chronic bacterial infections and provides a model for dissecting pro- and anti-inflammatory cascades.