Background: Infectious diseases represent an important barrier to sustainable aquaculture development. Rearing density can substantially impact fish productivity, health and welfare in aquaculture, including growth rates, behaviour and, crucially, immune activity. Given the current emphasis on aquaculture diversification, stress-related indicators broadly applicable across species are needed. Results: Utilising an interspecific comparative transcriptomic (RNAseq) approach, we compared gill gene expression responses of Atlantic salmon (Salmo salar) and Nile tilapia (Oreochromis niloticus) to rearing density and Saprolegnia parasitica infection. Salmon reared at high-density showed increased expression of stress-related markers (e.g. c-fos and hsp70), and downregulation of innate immune genes. Upon pathogen challenge, only salmon reared at low density exhibited increased expression of inflammatory interleukins and lymphocyte-related genes. Tilapia immunity, in contrast, was impaired at low-density. Using overlapping gene ontology enrichment and gene ortholog analyses, we found that density-related stress similarly impacted salmon and tilapia in key immune pathways, altering the expression of genes vital to inflammatory and Th17 responses to pathogen challenge. Conclusions: Given the challenges posed by ectoparasites and gill diseases in fish farms, this study underscores the importance of optimal rearing densities for immunocompetence, particularly for mucosal immunity. Our comparative transcriptomics analyses identified density stress impacted immune markers common across different fish taxa, providing key molecular targets with potential for monitoring and enhancing aquaculture resilience in a wide range of farmed species. species' health, welfare, and productivity. Rearing density is considered one of the pivotal factors determining aquaculture productivity and profitability (5-7). While overcrowding and/or under-stocking can significantly impact overt measures of fish performance such as growth rate (8, 9), size uniformity (10), and aggressive/unwanted behaviours (11-13), it can also adversely affect less obvious physiological parameters such as stress levels (9, 14), circulating hormones (14, 15), and flesh quality/composition (16). It is increasingly apparent that suboptimal rearing densities have negative consequences for fish immunity (17-19) and thus increase susceptibility to pathogens (10, 20). Infectious disease is currently one of the greatest barriers to sustainable aquaculture intensification (21), and a substantial economic burden on the industry (22). Therefore, it is important to know if the underlying effects of rearing density on fish health are conserved across fish species, and whether broadly applicable key stress indicators can be applied for management of density-related stress in aquaculture. RNAseq methods have proved valuable tools for assessing the wider impacts of environmental stressors and pathogens on animal health at the functional genomic level (23-25). Interspecific comparative t...