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The purpose of the present work is to investigate the anisotropy in the contact response of f.c.c and h.c.p single crystals. To this aim, spherical indentation experiments were simulated at a meso-scale, which is relevant to the interpretation of instrumented indentation experiments and micro-hardness tests in bulk single crystals and coatings. Within this framework, both the instrumented indentation load (
P)-penetration depth (
h
s) curves and the pile up or sinking-in patterns developed around the indentation imprint were analyzed. The detailed assessment of plastic zone morphology and plastic strain localization features was also addressed to complete the micro-mechanical analysis of indentation experiments. An important outcome from the present work is the identification of very specific and orientation dependent locations within the film–substrate interface, where plastic strain localizes as indentation proceeds. These findings can be significant on the prediction of delamination and potential failure of coatings and thin films.