Heart and skeletal muscle inflammation (HSMI) is a significant disease affecting Atlantic salmon (Salmo salar) production in Norway but has had limited impact to production in North America. The causative agent of HSMI is piscine orthoreovirus genotype 1 (PRV-1), and disease variation between regions is suggested to be at least partially driven by genetic variation of the virus. Using controlled laboratory injection challenges, we corroborate variations in disease outcomes for three PRV-1 isolates (PRV-1a from the eastern Pacific, PRV-1a from the western Atlantic, and PRV-1b from the Norwegian sea); however, virus replication dynamics, host recognition, and PRV-1-associated heart inflammation were also discrete relative to the Atlantic salmon stock challenged, irrespective of the viral isolate used. Specifically, New Brunswick Tobique River Atlantic salmon had less (p < 0.01) heart inflammation relative to Mowi-McConnell Atlantic salmon of Western Canada which, in turn, had less (p < 0.01) heart inflammation than Mowi Atlantic salmon of Scotland when cumulatively considering challenges using all three PRV-1 isolates. These data indicate that the presence of PRV-1a or PRV-1b alone is not sufficient to reliably predict disease and highlights at least one potential mechanism (host genotype) for reducing HSMI disease severity.