In the context of mass mortality outbreaks affecting adult and juvenile mussels since 2014 in France, two investigations were conducted to study mussel mortality under laboratory conditions in 2015. The first investigated the horizontal transmission of a putative causal agent of the mortality among two stocks of wild Mytilus edulis and the potential genetic resistance of adults and their progenies. The second evaluated the resistance of pure and hybrid crosses of M. edulis and M. galloprovincialis at the spat stage to a mortality outbreak. For the first time in France, we described several mortality outbreaks affecting spat and adult mussels under laboratory conditions. Mortality was observed for seawater temperatures ranging from 10 to 23 °C, although the significant mortality outbreaks occurred between 12 and 17 °C in adults and at 22 °C in spat. The disease screening revealed that no notifiable pathogen agent, as defined by OIE, was detected in the analyzed moribund mussels. Although bacteria belonging to the Splendidus clade were detected at high prevalence, with the exception of a mortality outbreak occurring in August, their role could not be defined in this study. Survivors of a mortality event occurring in the field in 2014 (Yves stock) still exhibited around 30% of mortality in 2015 under laboratory conditions, which indicated that they were either not fully resistant or that susceptibility varies with mussel age/size. This finding also suggests that a part of the survivors (or all) were carriers of a putative causal agent of the mortality. We demonstrated the horizontal transmission of a putative causal agent from the Yves stock to another stock of wild adult mussels (stock Agnas) which experienced 46% of mortality. In contrast, the Agnas stock had low mortality (5%) in the separate condition. Horizontal transmission of a putative causal agent from the wild adults to their hatchery-produced progenies was also observed. The progenies of the Yves stock, which survived a mortality outbreak in 2014, had lower mortality (27%) than those of the unselected Agnas stock (68%). Similarly, low mortality (<20%) were reported at the spat stage for a second stock of M. edulis produced from survivors of a mortality outbreak as well as for M. galloprovincialis, whereas their interspecific hybrids had mortality around 30%. These results could suggest that selective breeding programs in M. edulis, or the cultivation of M. galloprovincialis rather than M. edulis, could both reduce the impact of mortality outbreaks on mussel aquaculture. Nevertheless, further investigations are required to address the genetic basis of the survival in the two main mussels species cultivated in France.