Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Although much is known about how soluble factors influence macrophage polarization, relatively little is known about how physical cues present in the extracellular environment might modulate proinflammatory (M1) vs. prohealing (M2) activation. Specifically, the role of cell shape has not been explored, even though it has been observed that macrophages adopt different geometries in vivo. We and others observed that macrophages polarized toward different phenotypes in vitro exhibit dramatic changes in cell shape: M2 cells exhibit an elongated shape compared with M1 cells. Using a micropatterning approach to control macrophage cell shape directly, we demonstrate here that elongation itself, without exogenous cytokines, leads to the expression of M2 phenotype markers and reduces the secretion of inflammatory cytokines. Moreover, elongation enhances the effects of M2-inducing cytokines IL-4 and IL-13 and protects cells from M1-inducing stimuli LPS and IFN-γ. In addition shape-but not cytokine-induced polarization is abrogated when actin and actin/myosin contractility are inhibited by pharmacological agents, suggesting a role for the cytoskeleton in the control of macrophage polarization by cell geometry. Our studies demonstrate that alterations in cell shape associated with changes in ECM architecture may provide integral cues to modulate macrophage phenotype polarization. Macrophages play an essential role in innate immunity and are involved in a variety of immune functions, including host defense and wound healing. In addition, these cells participate in the progression of many chronic inflammatory diseases. To fulfill their functionally distinct roles, macrophages are capable of polarizing toward a spectrum of phenotypes, which include classical (proinflammatory, M1) and alternative (anti-inflammatory, prohealing, M2) activation states, as well as a regulatory phenotype and subtypes of these broad classifications (1). In the presence of inflammatory stimuli and danger signals, macrophages polarize toward the M1 state and release reactive species and inflammatory cytokines to fight pathogens. In contrast, a wound healing environment promotes polarization toward an M2 phenotype and leads to cellular processes that facilitate tissue repair. Although distinct macrophage subpopulations are clearly observed at different phases of the immune response to infection and injury (2), regulation of phenotypic polarization of these remarkably plastic cells still remains poorly defined.Activated macrophages are derived from circulating monocytes or resident tissue macrophages and migrate through the extracellular space in response to chemotactic agents to reach the target wound or infection site. Although it is thought that cytokines and chemokines are the primary regulators of macrophage behavior (3), some recent studies suggest that tissue structure and physical cues in the extracellular environment also contribute to ...