We have investigated the sliding friction behavior of metallic couples with different enthalpy of mixing or reaction by friction force microscopy. Comparing the friction behavior of miscible and immiscible couples we find that in the first case friction is governed by adhesion while the shear strength is low ( τ = 3–6 MPa). In the latter case of immiscible couples, adhesion is found to be low and the shear strength is large ( τ ≈ 70 MPa). Statistical analysis of atomic stick-slip images recorded on an Au(111) surface with tips of different affinities with gold allows for a deeper understanding of our results. The periodicity of atomic stick-slip images corresponds to the interatomic distance of gold for immiscible counter-bodies. In contrast, for a reactive couple the periodicity of atomic stick-slip significantly differs from the gold interatomic distance and may correspond to the structural length of an ordered intermediate phase at the tip-surface interface.