Genotype-by-environment (GxE) interaction in aquaculture is usually estimated for continuous traits and based on data from a limited number of 2–3 rearing sites. Here we report the results of a GxE study for resistance to Pacific oyster mortality syndrome (POMS), a multi-factorial disease that severely impacts Pacific oyster production worldwide. The syndrome is largely associated with Ostreid Herpes Virus 1 (OsHV-1). Resistance to OsHV-1 in Crassostrea gigas has been shown to be heritable, meaning that selective breeding is a suitable strategy for reducing mortalities. However, limited information was available about GxE interaction or the possible need to consider it in selective breeding. Survival of two cohorts (C1 and C2), consisting of a total of 104 full-sib families, was evaluated during the summer of 2013 in 7 sites along the French Atlantic, Channel and Mediterranean coasts. Mean survivals in autumn 2013 were 12.6% ± 10.9 and 4.6% ± 6.4 for C1 and C2, respectively. Genetic parameters were computed by MCMC, which is suitable for binary data like survival. Heritability estimates ranged from 0.16 to 0.42 depending on site and cohort, with a mean of 0.24 [0.20; 0.27] when including all data. GxE interactions were estimated by the genetic correlations between pairs of sites. Genetic correlations were high ( > 0.80) for C1 between most tidal Atlantic and Channel sites, and intermediate between tidal sites and a Mediterranean lagoon site, while they were lower and more variable for C2 (0.21–0.77). Expected genetic gains were maximal when production site was the same as selection site. They were closed to this expected maximum when the selection site was different from the production site along the Atlantic or Channel coast. Limited GxE interaction along the French Atlantic coast is favorable to wide dissemination of genetically improved oysters along this coast. Limited potential improvement was shown in the Mediterranean site if selection was carried out elsewhere, confirming the specificity of this environment. Consequently, a specific strategy such as dedicated breeding should be used to achieve genetic progress for this site.