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Health diets for Atlantic salmon have become an important component of the integrated pest management strategies targeting sea lice. A challenge trial was performed to examine the effect of supplementing salmon diets with either immunostimulants or essential oils. One control and four experimental diets containing immunostimulants or natural identical extracts were fed to Atlantic salmon in triplicate tanks for 4 weeks before challenging the fish with the sea lice copepodids. Prevalence of infection was 100%, and the mean abundance of infection was 21.2. The lowest mean lice count of 17 per fish (P < 0.05) was found in the group fed a mix of natural identical plant extracts (PX I). This represents a 20% reduction in infection, showing the potential for health diets to be employed as a tool to help control sea lice. To gain an understanding of the mechanisms of action underlying this protection, fish fed the control diet and fish fed the PX I diet were compared using quantitative histology of the epidermis and proteomic analysis of epidermal mucus. No significant differences were seen in the thickness of the epidermis or mucous cell percentage area, but differences in expression were seen for a number of proteins, including heat shock proteins, in epidermal mucus.