Background:In recent years, the aquaculture industry of Crassostrea gigas has been severely impacted by geographically widespread outbreaks of a polymicrobial disease, the Pacific Oyster Mortality Syndrome (POMS). The aetiology of these recurring summer mortality events and the disease progression have notably been recently described in France, revealing a combined development of viral (namely the Ostreid Herpesvirus, OsHV-1 µVar) and bacterial infections. In New Zealand (NZ), mass mortality episodes associated with OsHV-1 have been recorded in juvenile C. gigas since 2010 and selective breeding to improve resistance to OsHV-1 has been effectively used to mitigate the impact of the disease. However, POMS infection process and the role of the host-microbiota during infection have still not been well established in NZ. Results:Using a laboratory-based experimental infection approach, we challenged ten biparental oyster families with previously established contrasted genetically based ability to survive POMS in the field. Molecular analyses (viral load quantification, viral gene expression and 16S rRNA gene sequencing) were combined with histopathological observations to describe the temporal kinetics of infection to POMS and to characterize the role of microbiota during infection. Our main findings showed (1) a delay in viral infection resulting in a late onset of mortality in oysters compared to previous observations from France, and (2) a lack of evidence of major fatal bacteraemia in infected oysters. Bacterial profiling associated the microbiota composition with mortality rate, viral load, and viral replication, allowing the identification of potentially deleterious and beneficial bacterial taxa that can influence the outcome of the disease. Mycoplasma ASV-1 was identified as a significant predictor of mortality in oysters. Conclusion:Collectively, these results could improve current disease management and aquaculture practices and help understanding the mechanisms behind genetic resistance to POMS. Ultimately, microbiome composition could be used to predict oyster mortality following exposure to OsHV-1 and be used as a complementary screening tool in selective breeding and/or a diagnostic tool to determine shellfish health.