Atlantic salmon is the only species in which the disease infectious salmon anaemia (ISA) has been observed naturally. Initial reports of findings of infectious salmon anaemia virus (ISAV) before 2002, did not distinguish between non virulent HPR0 and virulent HPRΔ viruses, thus making interpretation of older findings difficult in the light of current knowledge. Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the relationship between HPR0 and HPRΔ, the risk of HPRΔ ISAV emerging from HPR0 ISAV, and possible risk factors for such an emergence. HPR0 ISAV does not cause clinical disease in Atlantic salmon; however, it causes a transient subclinical infection and replicates mainly in gills. There is no evidence for HPR0 ISAV leading to natural infection and replication in fish species other than Atlantic salmon. Virulent ISAV have deletions in the HPR region of the HE gene and they have either an insertion or the Q266L mutation in the F gene. The most plausible hypothesis is that virulent ISAV (HPRΔ) is derived from HPR0 ISAV. This is further supported by the close association between the genetic relatedness and spatio-temporal distances of virus strains in solitary outbreaks. Epidemiological and historical data from solitary disease outbreaks indicates that the risk of HPRΔ ISAV emerging from HPR0 is low, but not negligible. The risk factors for HPRΔ emergence from HPR0 are unknown. Nevertheless, any factor that affects virus replication or host susceptibility could possibly influence the risk of emergence. More research is needed on the drivers for transition from HPR0 to HPRΔ and factors affecting host susceptibility and thereby emergence of clinical disease. A quantitative assessment of the different evolutionary forces for ISA would be useful, as well as the prevalence of ISAV HPR0 in farmed and wild Atlantic salmon.