Mechanical behavior and fracture mechanisms of plasma sprayed hydroxyapatite coatings on Ti-6Al-4V substrate were assessed taking into consideration two variables: the coating thickness and the substrate roughness. The results show that the specimens having a substrate arithmetic average roughness parameter Ra = 2.29 µm is favorable with respect to Ra = 1.23 µm. For coating thickness above 105 µm, cracks can be observed in the coating/substrate interface and the higher critical load Pc2 (used generally in comparative evaluation of adherence) decreases. A 90 µm coating thickness sprayed on a substrate having an arithmetic average roughness parameter Ra equal to 2.29 µm seems to be the best compromise between microstructure, mechanical resistance (high critical loads and fairly good contact quality) and long term stability in the physiological medium (low dissolution rate) for an orthopedic application.