BACKGROUND: Adenosine is a ubiquitous endogenous molecule capable of influencing several pathophysiological aspects. The adenosine system is extremely complex, starting from the generation of intracellular and extracellular adenosine, the regulation of its levels, and its action on four different receptors that vary in affinity and distribution in the different cell types and tissues. The most relevant effects of adenosine during infections and inflammation are documented on all types of immune cells, including those of adaptive immunity (T lymphocytes, B lymphocytes, regulatory cells) and of natural immunity (macrophages, polymorphonuclear cells, dendritic cells, natural killer). Of interest, the adenosine system is also strongly involved in the pathophysiology of colonic cells. Clostridioides difficile (C. difficile), responsible for 15-20% of all cases of antibiotic-associated diarrhea, is an infection that has been evolving over the past two decades due to the unstoppable spread of C. difficile in the anthropized environment and the progressive human colonization. The pathological activity of C. difficile is due to toxin A (TcdA) and B (TcdB) which profoundly alter the homeostasis of the adenosine system, acting both at the level of its generation and on the expression and regulation of adenosine receptors. The final effect consists in an attenuation of the inflammatory response to favor the persistence of the C. difficile infection. CONCLUSION: This review highlights a new ability of C. difficile, through its Tcds, of manipulating the host to its advantage.