Piscirickettsiosis (SRS) is the most prevalent bacterial disease in Chilean salmon aquaculture and is responsible for high economic losses. The aim of this study was to comparatively characterize the pathogenesis of SRS in post-smolt Atlantic salmon during the early and late stages of infection with Piscirickettsia salmonis LF-89-like (PS-LF-89) and EM-90-like (PS-EM-90) using a cohabitation challenge. The pathogenesis of cohabitant fish infected with the two isolates was relatively different due to cohabitant fish infected with PS-EM-90 showing higher cumulative mortality and shorter time until death compared with PS-LF-89 fish. PS-LF-89 caused an SRS infection characterized by kidney and liver lesions, whereas PS-EM-90 caused systemic and haemorrhagic disease characterized by kidney, liver, heart, brain, skeletal muscle and intestine lesions. Decreased serum concentration of total proteins and albumin as well as increased serum ALT, AST and creatinine levels in fish infected with both isolates confirmed that changes in liver and kidney function occurred during infection. Tissue damage, expressed as an SRS histoscore, showed a strong positive correlation with the bacterial load expressed as abundance of P. salmonis 16S rRNA transcripts in the livers and kidneys of fish affected with either isolate, but the correlation was significantly higher in fish infected with PS-EM-90. The results contribute to improving the understanding of the bacteria–host interaction.