To improve sustainability of aquaculture, especially for carnivorous species like Atlantic cod, replacement of fish oil-based diets with vegetable oil-based diets has been studied. The use of vegetable oil in fish feeds can significantly change the fatty acid composition of fish tissues, and given the importance of fatty acids in inflammation and immunity, this change could potentially impact the immune response and health of the fish. The oilseed Camelina sativa is a promising source for this vegetable oil, because of the high oil content of its seeds (40%), a higher n-3 fatty acid content than most other oilseeds, and a high amount of γ-tocopherol. This study aims to investigate the effect of the replacement of dietary fish oil with oil from Camelina sativa on the immune response of Atlantic cod, as measured by the gene expression in spleen.Juvenile cod were fed on a fish oil-based diet (FO) or one of two diets in which camelina oil replaced 40% or 80% of fish oil (40CO and 80CO respectively) for 67 days, after which they were injected with either the viral mimic polyriboinosinic polyribocytidylic acid (pIC), or phosphate-buffered saline (PBS) as a control. Microarray analysis was used to determine the effect of the diet on the basal spleen transcriptome (pre-injection), and on the response to pIC (24 h post-injection). No marked differences in the spleen transcriptome were found between the three diets, either before or after injection with pIC. All fish, regardless of diet, showed a strong anti-viral response 24 h after pIC injection, with more than 500 genes having a significant difference of expression of 2-fold or higher compared to the PBS-injected fish for the FO, 40CO and 80CO diets. Gene Ontology annotation analysis of the three pIC-responsive gene lists indicated they were highly similar, and that the term ‘immune system process’ was significantly enriched in the pIC-responsive gene lists for all three diets. QPCR analysis for 5 genes with a known function in the anti-viral innate immune response (LGP2, STAT1, IRF1, ISG15 and viperin) showed modestly (smaller than 2-fold) up-regulated basal expression of LGP2, IRF1 and STAT1 in fish fed 40CO compared to the other diets. After pIC injection, all 5 genes were significantly and strongly up-regulated in pIC-injected fish compared to PBS-injected fish, but no significant differences were found between any of the diets.In conclusion, replacement of up to 80% of fish oil with camelina oil in Atlantic cod diets does not have a strong effect on basal spleen gene expression. Atlantic cod fed on camelina oil-containing diets are capable of mounting a strong anti-viral immune response, which is comparable to that in cod fed with a fish oil diet.