Hydrothermal vent mussels belonging to the genus Bathymodiolus dominate communities at hydrothermal sites of the Mid-Atlantic Ridge. The mussel Bathymodiolus azoricus harbors thiotrophic and methanotrophic symbiotic bacteria in its gills and evolves in naturally highly metal contaminated environments. In the context of investigations on metal tolerance/effect in B. azoricus, we focused our work on the short-term adaptive response (15days) of mussels to different metals exposure at a molecular level using metal concentrations chosen to mimic natural situations at three vents sites. The expression of a set of 38 genes involved in different steps of the metal uptake, detoxication and various metabolisms was analysed by qPCR. Mussels were also genotyped at 10 enzyme loci to explore the relationships among natural genetic variation and gene expression. Relation between symbiont content (both sulfur-oxidizing and methanogen bacteria) and gene expression was also analysed. Our study demonstrated the influence of metal cocktail composition and time exposure on the transcriptome regulation with a specific pattern of regulation observed for the three metal cocktail tested. We also evidenced the significant influence of some specific Pgm genotype on the global gene expression in our experimental populations and a general trend of a higher gene expression in individuals carrying a high symbiont content.