The ectoparasitic copepod, Lepeophtheius salmonis, is considered to be the most economically damaging parasite in commercial Atlantic salmon (Salmo salar) culture, causing serious disease outbreaks which cost the industry nearly half a billion dollars annually. While other salmonid species show some resistance to this parasite, Atlantic salmon have previously shown very little in the way of inflammatory response to sea lice infection. The objective of this study was to enhance the immune response of Atlantic salmon to sea lice infection through the administration of in-feed immunostimulants. The efficacy of dietary additives to stimulate the immune response of Atlantic salmon against L. salmonis was evaluated over three trials. Trial 1 tested three immunostimulants: ProVale (B-glucan), All Brew/ Nupro (commercial yeast extracts) and CpG ODN during a low-level sea lice exposure in Atlantic salmon. Fish fed CpG ODN showed the greatest reductions in sea lice, which was accompanied by an increase in inflammation observed in histological sections of the lice infection. Up-regulation of IL-1B; and MMP 9 was also observed in CpG ODN fed fish following sea lice exposure. All Brew/ Nupro was also found to be effective at reducing the final sea lice burden though these reductions did not correlate to changes in tissue response or gene expression. The ProVale additive was not effective at reducing infection levels at the dose administered. Trial 2 investigated whether CpG ODN, administered at half the original dose and for a shorter time, could enhance acquired immune responses following experimental re-infection with L. salmonis. Both the previously infected control and CpG ODN fed fish showed greater reductions in sea lice abundance indicating that prior exposure to sea lice offered some protective benefits during re-infection. Sea lice reductions in the CpG ODN fed group exceeded the previously infected control indicating that treatment with CpG ODN conferred protection beyond prior exposure alone and may contribute to the activation of adaptive immunity in Atlantic salmon. The objective of Trial 3 was to compare the effects of dose during a low level sea lice infection using a commercial mixture of immunostimulants, administered at a high and low dose. The low dose reduced the sea lice burden in infected salmon by 48% while the high dose provided little protective benefit. No differential gene expression was observed in this trial, thus leaving the mechanism for dose related responses of these treatments unknown. Overall, this study demonstrated the effectiveness of CpG ODN as a dietary immunostimulant during both primary and secondary exposure to sea lice and illustrated the importance of dose to the effectiveness of boosting innate immunity. Furthermore, the immune genes IL-1B; and MMP 9 were identified as being involved in the early inflammatory response and wound healing and are likely associated with increased resistance following oral administration of CpG ODN. Incorporation of immunostimulants into future sea lice reduction protocols, either alone or in conjunction with existing methods and treatments is likely to have direct benefits to Atlantic salmon farm management strategies.