Hydrothermal vents and methane seeps are extreme deep-sea ecosystems that support dense populations of specialised macrobenthos such as mussels. But lack of genome information hinders understanding of the adaptation of these animals to such inhospitable environment. Here we report the genomes of a deep-sea vent/seep mussel Bathymodiolus platifrons and a shallow-water mussel Modiolus philippinarum. Phylogenetic analysis shows that these mussel species diverged approximately 110.4 million years ago. Many gene families, especially those for stabilising protein structures and removing toxic substances from the cells, are greatly expanded in B. platifrons, indicating adaptation to extreme environmental conditions. The B. platifrons innate immune system is considerably more complex than that of other lophotrochozoan species including M. philippinarum, with significant expansion and high expression of gene families related to immune recognition, endocytosis and caspase-mediated apoptosis in the gill, revealing presumed genetic adaptation of the deep-sea mussel to the presence of its chemoautotrophic endosymbionts. A follow-up metaproteomic analysis of the gill of B. platifrons found methanotrophy, assimilatory sulfate reduction, and ammonia metabolic pathways in the symbionts, providing energy and nutrients to allow the host to thrive. Our study of the genomic composition allowing symbiosis in extremophile molluscs gives wider insights into the mechanisms of symbiosis in other organisms such as deep-sea tubeworms and giant clams.