The ability to engineer biomaterial surfaces that are capable of a dynamic interaction with cells and tissues is central to the development of medical implants with improved functionality. An important consideration in this regard is the role played by the extracellular proteins that bind to an implant surface in vivo. Deliberate use of an ad-layer of such proteins on an implant surface has been observed to guide and direct cell response. However, the role that changes in surface topography might play in determining the nature of this cell–protein–surface interaction has not been investigated in detail. In this study, calcium phosphate (CaP) thin films have been deposited onto substrates with varying topography such that this is reflected in the (conformal) CaP surface features. A fibronectin (FN) ad-layer was then deposited from solution onto each surface and the response of MG63 osteoblast-like cells investigated. The results revealed that in all cases, the presence of the adsorbed FN layer on the CaP thin films improved MG63 cell adhesion, proliferation and promoted early onset differentiation. Moreover, the nature and scale of the response were shown to be influenced by the underlying CaP surface topography. Specifically, MG63 cell on FN-coated CaP thin films with regular topographical features in the nanometer range showed statistically significant differences in focal adhesion assembly, osteocalcin expression and alkaline phosphase activity compared to CaP thin films that lacked these topographical features. As such, these data indicate that surface topography can be used to further influence cell adhesion and downstream differentiation by enhancing the effects of a surface adsorbed FN layer.