Surface nanotopograpy has been recognized as an important regulator of cellular responses including those of immune cells, the latter being of particular importance for implantable materials since these can determine biomaterial fate. In this paper, evidence is provided that the scale of surface nanotopography modulates the conformation of attached serum proteins, which in turn controls immune cell adhesion and activation. Model surfaces of tailored nanotopography of heights of 16, 38, and 68 nm are created by covalent immobilization of gold nanoparticles to an oxazoline‐rich plasma polymer film. This strategy not only produces surfaces of tailored nanofeature density but allows control of the outermost surface chemistry. Circular dichroism spectroscopy and Mac‐1 positive THP‐1 monocytes studies demonstrate distinct protein unfolding patterns, which upregulate or downregulate the expression of proinflammatory cytokines and cells attachment. The findings presented in this paper shed light on the missing relationship between surface nanotopography, protein unfolding, and the immune response. On the other hand, this work demonstrates the possibility to use specifically tailored surface nanotoporaphy scales to modulate and achieve desired immune responses.