Massive spring mortality outbreaks have been reported in Mytilus spp. in France since 2014. The main areas affected are the Pertuis Charentais Sounds and the coast of the Pays de la Loire, which cultivate mainly M. edulis, and the putative causal agents remain unknown. We report the results of the first generation of mass selection focused on survival and resistance to the spring mortality in M. edulis. Two stocks of mussels were sampled in the Pertuis Charentais Sounds in 2014; one of these went through a spring mortality outbreak and the survivors were used to produce the selected stock, while the second stock was M. edulis considered to be naïve against the putative causal agents of the mortality outbreak and was used to produce the control stock. A first cohort was produced in 2015 and tested at one site in the Pertuis Charentais Sounds. In April and May 2016, a spring mortality outbreak was observed when seawater temperature ranged from 10 to 15 °C. In October 2016, the selected stock had a lower mortality (44%) than the control stock (78%). To confirm this result and investigate genotype by environment interaction, a second cohort was produced in 2016 and tested at six sites. Although no significant mortality was reported at the four sites in the Pertuis Charentais Sounds in 2017, the selected stock had a lower mortality (17–27%) than the control stock (61–74%) at the two sites along the coast of the Pays de la Loire. The survival had increased of 34–48% after one generation of mass selection and the realized heritability was high, ranging from 0.55 to 1.15, but further generations of selection are required to obtain a better estimation of the heritability. Our study showed a positive response to selection in three environments that were different to the site from which mussels were selected, suggesting the absence of strong genotype by environment interaction in sites where spring mortality outbreaks occurred. Selection to enhance M. edulis survival of the spring mortality should be efficient and should be capable of easy implementation through mass selection. Apparently, selection to enhance the survival of M. edulis did not affect the mussel growth in comparison with the controls, but automatically improved the yield of M. edulis in sites affected by the spring mortality outbreaks.