Medical implants are widely used nowadays. Following tissue contact, proteins adhere to the device's surface and surrounding cells become activated, causing an initial inflammatory host response. If this host response develops into a chronic inflammatory state, significant adverse effects such as implant rejection and loss might occur. The physico-chemical qualities of the biomaterials employed have a substantial influence on the degree of the immune response. Therefore, modulating surface properties such as topography or wettability may be a viable strategy for altering the immune response. However, the complex interrelation between surface properties, highly sensitive adsorption of proteins, and multifaceted immune response remains largely unresolved. This thesis aims at investigating the interplay of all three of these critical factors determining a device's biocompatibility in order to enable effective modulation of the immune response to biomedical implants. In the first part of this thesis, investigation of the contributing role of different immune cell types identified monocytes/macrophages as essential mediators of the initial inflammatory response, while involvement of T and NK cells was just minor during this phase. Analysis of titanium dental implant specimen revealed surface-dependent immune responses related to wettability and roughness. In contrast, systematic analysis of the influence of surface roughness of polymer materials in the second part of the thesis showed similar immunological activation irrespective of the applied surface roughness throughout the tested range. This was independent of the biological complexity of the cell culture system used (macrophage cell line, PBMCs, whole blood). The final section of the thesis examined wettability-mediated effects on immune cell activity using PEM coatings and discovered that pro- and anti-inflammatory cytokine responses are highly dependent on wettability, with lower pro-inflammatory effects reported on the more hydrophilic PEM surface. Experiments using serum-free cell culture medium demonstrated that the observed effects are clearly dependent on the presence of serum proteins at the biomaterial surface. Significant changes in the type and amount of adsorbed proteins were discovered using mass spectrometry analysis. The observed immunological differences could be correlated with the presence of specific apolipoproteins at the surfaces, implying that apolipoproteins might play a significant role in the modulation of biomaterial immune responses. These findings may aid in the targeted design of immunomodulatory surfaces to promote healing and implant integration. In addition, they place a larger emphasis on adsorption of proteins such as apolipoproteins as crucial class of immune cell mediators.