Lumpfish (Cyclopterus lumpus) is the most utilized cleaner fish in the North Atlantic salmon (Salmo salar) aquaculture industry. Lumpfish preys on the ectoparasite sea lice (e.g., Lepeophtheirus salmonis), one of the major threats to salmon farming worldwide. Lumpfish perform well in cold environments, and it has been commercially utilized as sea lice biocontrol since 2013 in Norway and since 2017 in Atlantic Canada. A healthy population of lumpfish could be used during two production cycles of Atlantic salmon. Bacterial infectious diseases are the most frequent health issues of lumpfish that impact its performance and extended utilization. We have developed several bacterial infectious disease models in lumpfish for vaccines and bacterial pathogenesis studies. Here, lumpfish immunity and infection to Piscirickettsia salmonis are examined and discussed. P. salmonis a facultative intracellular Gram-negative bacterium, which is the etiological agent of salmonid rickettsial septicemia (SRS), a disease that causes significant losses in the salmon farming industry and infect lumpfish. Nevertheless, this pathogen is not limited to only salmonid species, since the first report of SRS in lumpfish, no more information is available about the pathogenesis of P. salmonis in lumpfish. To unveil P. salmonis infection kinetics and disease on lumpfish, an appropriate infection model needs to be studied. Here, we develop a model infection for lumpfish. Lumpfish were infected intraperitoneally with three doses of P. salmonis (low, mid, and high doses), monitored for 90 days, samples of head kidney and spleen were taken for RNA-sequencing and histology. P. salmonis infection in lumpfish showed over 98 % mortality, and differences between doses only showed a delay in mortality. A total of 3047 differential expressed genes (DEG) were identified at 21 days post-infection (dpi) in the head kidney and 1551 in the spleen, at 35 dpi showed 910 DEG in the head kidney and 3761 in the spleen. Gene ontology analysis showed enrichment in negative regulation of antimicrobial peptide production, nucleate erythrocyte maturation, natural killer cell differentiation involved in immune response, protection from natural killer mediated cytotoxicity, regulation of neutrophil differentiation, positive regulation of type IV hypersensitivity, and positive regulation of plasma cell differentiation at 21 dpi, at 35 dpi interestingly enrichment analysis showed the same enriched pathways, but except negative regulation of antimicrobial peptide production, probably the genes involved in this pathway could be essential to overcome P. salmonis infection.