Fish red blood cells (RBCs) are nucleated and metabolically active with physiological and immunological properties. Salmonid RBCs are target cells of Piscine orthoreovirus (PRV), a double-stranded RNA virus with three known genotypes (PRV-1, 2 and 3). PRV-1 can give heart and skeletal muscle inflammation to farmed Atlantic salmon, which can lead to mortality in combination with stress, PRV-3 is non-pathogenic and cross-protective, whereas PRV-2 replicates less efficiently and protection is limited. The hypothesis is that RBCs respond differently to viruses depending on pathogenicity, that they respond to stress hormones, and that stress hormones inhibit their antiviral responses. Paper I demonstrated that RBCs express genes involved in pathogen recognition, chemotaxis and regulation of antiviral immunity. Comparing RBC responses to PRV-1 ex vivo with non-susceptible Atlantic salmon cell lines, revealed that RBCs expressed a specific repertoire of genes associated with viral dsRNA sensing and non-canonical IRF1-signaling, which could be associated with increased susceptibility to PRV. Paper II explored transcriptional differences in A. salmon blood cells post injection with different PRV genotypes. PRV-1 and PRV-3 replicated well in blood cells, but PRV-3 induced a potent antiviral response weeks earlier than PRV-1. This delay could increase the dissemination potential for PRV-1 and lead to increased pathogenicity. In contrast, PRV-2 and InPRV-1 primarily activated genes associated with intracellular signaling and protein trafficking. Paper III showed that exposure of RBCs to dexamethasone ex vivo led to >100-fold increase in FKBP prolyl isomerase 5 (FKBP5) and DNA damage-inducible transcript 4 protein (DDIT4) gene expression, while suppressing genes involved in antiviral immunity and proteolysis. A comparison with cortisol-treated A salmon in vivo revealed that DDIT4 could be a putative stress biomarker. These findings strengthen the notion that A. salmon RBCs are key mediators of antiviral and stress responses, while the specificity of their responses may have diagnostic potential.