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Controlling macrophage behavior has become a high-potential target strategy for regenerative therapies, such as in situtissue engineering (TE). In situTE is an approach, in which acellular resorbable synthetic scaffolds are used, to induce endogenous tissue regeneration. However, little is known regarding the effect of the biomechanical environment on the macrophage response to a scaffold. Therefore, the aim of this study was to assess the effect of cyclic strains (0%, 8%, and 14% strain) on primary human macrophage polarization in electrospun scaffolds with two different fiber diameters in the micrometer range (4 μm or 13 μm). High strains led to a proinflammatory profile in terms of gene expression, expression of surface proteins, and cytokine secretion. These results were consistent for scaffolds with small and large fiber diameters, indicating that the effect of cyclic strain was not affected by the different scaffold microstructures. Notably, macrophages were identified as direct contributors of early secretion of extracellular matrix proteins, including elastin, which was deposited in a strain-dependent manner. These findings are instrumental for the rational design of scaffolds for in situTE and underline that immunomodulatory scaffolds for biomechanically loaded applications should be mechanically tailored, for example, in terms of stiffness and compliance, to support a desirable proregenerative macrophage phenotype.Impact StatementElectrospun elastomeric scaffolds are being used for a variety of in situtissue engineering applications, in which biomechanical loads play a dominant in vivorole, such as cardiovascular replacements (e.g., heart valve and blood vessel prostheses) and pelvic floor reconstruction. The findings of this study underline that immunomodulatory scaffolds for biomechanically loaded applications should be mechanically tailored, for example, in terms of stiffness and compliance, to support a desirable proregenerative macrophage phenotype. Moreover, this research contributes to the general understanding of pathophysiological macrophage phenotypes in cyclically strained tissues (e.g., atherosclerotic plaques), and their role in tissue regeneration and degeneration.