The foreign body reaction, characterized by the presence of macrophages and foreign body giant cells, is a critical response to the implantation of medical devices, prostheses, or biomaterials. This review focuses on the factors that modulate the interaction between macrophages and foreign body giant cells on synthetic surfaces, emphasizing the role of protein adsorption, monocyte/macrophage adhesion, macrophage fusion, and the impact of the foreign body response on biomaterials. The surface properties of biomaterials play a crucial role in modulating the foreign body reaction within the first two to four weeks post-implantation. Understanding this reaction is essential for ensuring the biocompatibility and safety of medical devices, as well as for tissue engineering and regenerative medicine. The review also discusses the inflammatory and wound healing responses to implanted materials, the recruitment and activation of macrophages, the formation of foreign body giant cells, and the consequences of this reaction on biomaterial degradation and device failure. Additionally, it explores the cross-talk between macrophages/foreign body giant cells and inflammatory/wound healing cells, including cytokine secretion and extracellular matrix remodeling.The foreign body reaction, characterized by the presence of macrophages and foreign body giant cells, is a critical response to the implantation of medical devices, prostheses, or biomaterials. This review focuses on the factors that modulate the interaction between macrophages and foreign body giant cells on synthetic surfaces, emphasizing the role of protein adsorption, monocyte/macrophage adhesion, macrophage fusion, and the impact of the foreign body response on biomaterials. The surface properties of biomaterials play a crucial role in modulating the foreign body reaction within the first two to four weeks post-implantation. Understanding this reaction is essential for ensuring the biocompatibility and safety of medical devices, as well as for tissue engineering and regenerative medicine. The review also discusses the inflammatory and wound healing responses to implanted materials, the recruitment and activation of macrophages, the formation of foreign body giant cells, and the consequences of this reaction on biomaterial degradation and device failure. Additionally, it explores the cross-talk between macrophages/foreign body giant cells and inflammatory/wound healing cells, including cytokine secretion and extracellular matrix remodeling.