This study aimed at assessing the pathogenicity of two Vibrio splendidus‐related species and evaluating the influence of the origin and annual life cycle of mussels on their sensitivity during a bacterial challenge. Thus, in vivo infection assays were made with Vibrio crassostreae 7T4_12 and Vibrio splendidus 3G1_6, over, respectively, thirteen and 9 months, on adult blue mussels from five recruitment areas in France. Two bacterial concentrations were tested: one consistent with the loads of Vibrio spp. in environment and mussel tissues (~105 CFU/ml) and another one much higher (~108 CFU/ml). The tested environmental concentration has no pathogenic effect whatever the time of year, the strain used and the origin of mussels. However, at the highest concentration, a pathogenic effect was observed only at specific moments, and one of the origins appeared to be more resistant. The physiological state of mussels—depending on the time of year—seemed significant in mussels’ sensitivity, as their recruitment origin. This study is the first to test the pathogenicity of V. splendidus‐related strains at concentrations close to what is found in the wild, over the annual cycle of mussels, and considering their origin.