Recent studies have pointed towards a decisive role of inflammation in triggering tissue repair and regeneration, while at the same time it is accepted that an exacerbated inflammatory response may lead to rejection of an implant. Within this context, understanding and having the capacity to regulate the inflammatory response elicited by 3D scaffolds aimed for tissue regeneration is crucial. This work reports on the analysis of the cytokine profile of human monocytes/macrophages in contact with biodegradable 3D scaffolds with different surface properties, architecture and controlled pore geometry, fabricated by 3D printing technology. Fabrication processes were optimized to create four different 3D platforms based on PLA, PLA/CaP glass or chitosan. Cytokine secretion and cell morphology of human peripheral blood monocytes allowed to differentiate on the different matrices were analyzed. While all scaffolds supported monocyte/macrophage adhesion and stimulated cytokine production, striking differences between PLA-based and chitosan scaffolds were found, with chitosan eliciting increased secretion of TNF-α, while PLA-based scaffolds induced higher production of IL-6, IL-12/23 and IL-10. Even though the material itself induced the biggest differences, scaffold geometry also impacted on TNF-α and IL-12/23 production, with chitosan scaffolds having larger pores and wider angles leading to a higher secretion of these pro-inflammatory cytokines. These findings strengthen the appropriateness of these 3D platforms to study modulation of macrophage responses by specific parameters (chemistry, topography, scaffold architecture).