Cold-water corals form vast reefs that are highly valuable habitats for diverse deep-sea communities. However, as the deep ocean is warming, it is essential to assess the resilience of cold-water corals to future conditions. The effects of elevated temperatures on the cold-water coral Lophelia pertusa (now named Desmophyllum pertusum) from the north-east Atlantic Ocean were experimentally investigated at the holobiont level, the coral host, and its microbiome. We show that at temperature increases of + 3 and + 5 °C, L. pertusa exhibits significant mortality concomitant with changes in its microbiome composition. In addition, a metagenomic approach revealed the presence of gene markers for bacterial virulence factors suggesting that coral death was due to infection by pathogenic bacteria. Interestingly, different coral colonies had different survival rates and, colony-specific microbiome signatures, indicating strong colony-specific variability in their response to warming waters. These results suggest that L. pertusa can only survive a long-term temperature increase of < 3 °C. Therefore, regional variations in deep-sea temperature increase should be considered in future estimates of the global distribution of cold-water corals.