Infectious salmon anemia virus (ISAV) is an Orthomyxovirus challenging salmon production, with a particular impact in Chile. During 2007–2010 a devastating and of unexpected consequences epizootic event almost destroyed a blooming industry in the country. The event was caused by an aggressive variant with a distinctive deletion in Segment 6, one of the eight genomic segments of the virus. After the outburst, although the infective viral variant seemed to have disappeared, a non-infective variant, not previously reported, was discovered and is characterized by a complete, non-deleted coding segment 6, which has prevailed in the fish population until now. This variant, known as HPR0, appears to be the ancestor strain of ISAV from which novel infective variants are generated. Additional variations in segment 5 have also been associated with the virulence observed in the field, an analysis of the differences in these two protein coding segments has been performed. It appears to us that a combinatorial effect exists between the features displayed by segments 5 and 6 which modulate the intensity of viral outbursts. As a result, a theoretical integrative model is presented which explains the different degree of virulence observed in the field based only on molecular data, this could help estimating the intensity of damage a given variant might exert over a productive farm.