Background Symbiosis with chemosynthetic bacteria has allowed many invertebrates to flourish in ‘extreme’ deep-sea chemosynthesis-based ecosystems, such as hydrothermal vents and cold seeps. Bathymodioline mussels are considered as models of deep-sea animal-bacteria symbiosis, but the diversity of molecular mechanisms governing host-symbiont interactions remains understudied owing to the lack of hologenomes. In this study, we adopted a total hologenome approach in sequencing the hydrothermal vent mussel Bathymodiolus marisindicus and the endosymbiont genomes combined with a transcriptomic and proteomic approach that explore the mechanisms of symbiosis. Results Here, we provide the first coupled mussel-endosymbiont genome assembly. Comparative genome analysis revealed that both Bathymodiolus marisindicus and its endosymbiont reshape their genomes through the expansion of gene families, likely due to chemosymbiotic adaptation. Functional differentiation of host immune-related genes and attributes of symbiont self-protection that likely facilitate the establishment of endosymbiosis. Hologenomic analyses offer new evidence that metabolic complementarity between the host and endosymbionts enables the host to compensate for its inability to synthesize some essential nutrients, and two pathways (digestion of symbionts and molecular leakage of symbionts) that can supply the host with symbiontderived nutrients. Results also showed that bacteriocin and abundant toxins of symbiont may contribute to the defense of the B. marisindicus holobiont. Moreover, an exceptionally large number of anti-virus systems were identified in the B. marisindicus symbiont, which likely work synergistically to efficiently protect their hosts from phage infection, indicating virus-bacteria interactions in intracellular environments of a deepsea vent mussel. Conclusions Our study provides novel insights into the mechanisms of symbiosis enabling deep-sea mussels to successfully colonize the special hydrothermal vent habitats.