Skin aging and most age-related diseases are associated with a low-grade chronic inflammation. The nucleoside adenosine, a potent endogenous antiinflammatory agent, is deeply involved in inflammatory diseases and, by interaction with the adenosine A 2 receptor (A 2A R) it immediately promotes a mechanism of defence against the inflammatory damage. The aim of our study was to investigate whether polydeoxyribonucleotide (PDRN), a mixture of deoxyribonucleotides polymers of different lengths that like adenosine, binds the A 2A receptor, can reduce the inflammatory state in the macrophage cell line. RAW264.7, murine macrophage cells, were incubated with PDRN in the presence and in the absence of lipopolysaccaride (LPS), which was the major component of the outer membrane of gram-negative bacteria and which acted as a strong macrophage activator. We assessed the production of nitric oxide and the secretion of inflammatory mediators (i.e., TNF-α, IL-10, IL-12 and VEGF-A). Our data showed that PDRN produced a significant decrease of inflammation in macrophages pre-stimulated with LPS, assessed in terms of the nitric oxide content (p < 0.001) and cytokines secretion (p < 0.001). Moreover, PDRN stimulated the release of the vascular endothelial growth factor (VEGF-A), which promoted wound healing. Our study suggested that PDRN, by binding the A 2A receptor, contributed to a great extent towards reducing inflammation.