Fibrinogen adsorbed on material surfaces undergoes conformational changes and subsequently mediates platelet adhesion. Recent evidence has shown that the platelet binding epitope located in the y-chain dodecapeptide plays an important role in platelet adhesion to biomaterials. In this chapter, we describe a series of studies using an immuno-AFM technique employing an antibody-modified probe for measuring the probability of this y-chain dodecapeptide epitope (γ3 92-411) being available (a measure of protein functional activity) following fibrinogen adsorption to model material surfaces. AFM measurements show that the functional activity of fibrinogen appears to be both time and substrate dependent, with the surface characteristics and compositions of protein solution affecting the time dependence. The probability of antibody binding correlates well with temporal changes in platelet adhesion to these material surfaces, suggesting that the availability of the γ-chain in fibrinogen is a useful predictor of platelet adhesion. Results demonstrated that the utility of this approach for measuring protein function at or near the molecular scale and offers new opportunities for improved insights into the molecular basis for the biological response to biomaterials.