Biomaterial characteristics such as topography and wettability have been shown to influence the immune response to implanted medical devices. Thus, appropriate surface design considering the immune system has moved more into focus. Previous in vitro studies have commonly employed simplistic immune models and as such, the role of different immune cell populations, particularly those of the adaptive immune system, is still poorly understood. Here, we employed a biologically complex human-based in vitro model consisting of peripheral blood mononuclear cells (PBMC) to examine interactions between cells of the innate and adaptive immune system in the context of clinically used implants. To achieve this, five differently treated titanium surfaces were characterised in terms of physicochemical properties using contact angle measurement, XPS and confocal scanning microscopy. Cytokine analysis revealed different material surface properties to result in different immune responses with SLActive surface showing low levels of IL-6 and IL-8 but high levels of MCP-1. Cytokine and surface marker analysis in isolated populations of monocytes and lymphocytes and defined ratios revealed lymphocytes alone to be unaffected by the SLActive biomaterial and except for a slight effect on HLA-DR expression indicated no activation of monocytes by lymphoid cells. On lymphocytes, CD16 and HLA-DR expression was unaffected by monocytes under physiological conditions but was elevated with high levels of monocytes present. Intracellular cytokine staining in whole PBMC cultures confirmed monocytes to be responsible for the observed immune response, with minimal involvement of lymphocytes. Expression of the pro-inflammatory cytokines IL-8 and TNF-α in monocytes peaked 12 h after biomaterial contact, while the expression of surface markers HLA-DR and CD86 continued to rise 72 h following contact. These results collectively suggest the immune response to titanium biomaterials in the first 72 h in vitro to be almost exclusively driven by the innate rather than the adaptive immune system.