The aim of this work is to study the effects of the titanium plasma spray (TPS) coating process on the fatigue resistance of a titanium-6Al-4V substrate. The combination of TPS processes and Ti alloy substrate is widely applied on components intended for cementless total hip replacement (THR). In order to understand the coating process mechanism behind the implants’ fatigue resistance decrease, one air-developed coating (Ti-APS) and one controlled atmosphere developed coating (Ti-CAPS) were considered. The effects of the most representative parameters of the plasma spray process on the fatigue resistance were analysed: the sandblasting process, the plasma and the coating powder. Fatigue resistance studies were performed by means of rotating bending fatigue testing. After fatigue failure specimens underwent morphological analyses both on the primary crack surface and on the cross-sectional area complemented by of the metallographic analyses of the coating. The titanium substrate fatigue resistance decreased after being blasted with direct relationship with the grain size. Ti-CAPS process showed a relatively limited further influence on the fatigue resistance reduction with respect to only sandblasted samples. By contrary a remarkable fatigue limit decreased was seen for Ti-APS coated samples against Ti-CAPS and simply sandblasted samples. The experiment pointed out the critical importance of cracks oxidation as a fatigue failure driving factor.