Extracellular adenosine 5′-triphosphate (eATP) is an essential signaling molecule that mediates different cellular processes through its interaction with membrane-associated receptor proteins in animals and plants. eATP regulates plant growth, development and responses to biotic and abiotic stresses. Its accumulation in the apoplast induces ROS production and cytoplasmic calcium increase mediating a defense response to invading microbes. We showed that the root endophyte Serendipita indica can overcome this response by secreting the ecto-5`-nucleotidase SiE5’NT in the apoplast of its plant hosts. SiE5’NT hydrolyzes eATP to adenosine, functioning as a compatibility factor. Arabidopsis lines expressing extracellular SiE5’NT are significantly better colonized and have reduced eATP levels and defense responses compared to the control lines upon fungal challenge, suggesting that SiE5’NT serves as a tool for manipulation of host eATP signaling.