Objective: two major complications after arthroplasty are prosthetic joint infection, mainly due to Staphylococcus aureus, and the experience of a foreign body reaction by macrophages and foreign body giant cells (FBGCs) regardless of the infection. Our aim is to study the role of purinergic receptors with fusogenic function (P2X7, adenosine A1 and A2A receptors) in the formation of S. aureus-induced FBGCs and their possible differential modulation in the presence of Ti–6Al–4V and Cr-Co-Mo alloys. Methods: RAW264.7 cells were differentiated to FBGCs with 20 ng/mL of IL-4 in the presence of adhered unviable S. aureus, metal alloys and/or CGS21680/ZM241385 1 µM. Cell supernatant was collected for nucleotide analysis by HPLC as well as cytokine expression, and cells were lysed for RNA expression. Results: the presence of S. aureus induces an increase in FBGCs formation in a concentration-dependent manner. Furthermore, phalloidin staining demonstrated that both Ti–6Al–4V and Cr-Co-Mo alloys reduce the formation of FBGCs. The expression of adenosine A1 and A2A receptors increased after 5 days of differentiation in the presence of S. aureus, and this expression was enhanced with metal alloys. HPLC analyses showed an increase in adenosine in the presence of Ti–6Al–4V and Cr-Co-Mo alloys while ATP was not changed in any of the conditions. The presence of metal alloys induced an increased in IL1β, IL-6 and RANTES. Conclusions: the increased levels of adenosine and the adenosine A2A receptor induced by the presence of Ti–6Al–4V and Co-Cr-Mo alloys would be responsible for the inhibition of cell fusion and the following reduction of S. aureus-induced FBGCs., This work was supported by grants from Becas FEIOMM INVESTIGACIÓN 2021 and Instituto de Salud Carlos III through the “Miguel Servet” program (CP15/00053, CPII20/00017), co-funded by Fondo Europeo de Desarrollo Regional (FEDER), and a research grant from the Spanish Instituto de Salud Carlos III (PI19/00744, PI22/00347)., Peer reviewed