The present study demonstrates that farmed Atlantic salmon, Salmo salar, health is positively and significantly affected by synergistic effects between very long-chain polyunsaturated fatty acids of the n-3 family eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) and iron, where positive effects of high dietary levels of EPA/DHA are enhanced when combined with low levels of iron. Based on cumulative mortalities in the different experimental groups, relative percentage of survival (RPS) for the high EPA/DHA-low iron group was 70% during an outbreak of furunculosis and 96% during an outbreak of cold water vibriosis compared with the controls. A non-additive effect between EPA/DHA and iron was confirmed by statistical analyses that revealed a significant effect of EPA/DHA alone and an interaction of iron with EPA/DHA. Liver cell cultures treated with EPA/DHA revealed that the synergistic effect could be related to an EPA/DHA dependent regulation of mRNA for proteins important for transport (transferrin) and storage (ferritin) of iron in the salmon. In keeping with this finding, the transcriptional down-regulation of iron metabolism in vitro was reflected in decreased in vivo iron stores with increasing levels of dietary EPA/DHA. Hence, to avoid overloading of the iron transport/storage-systems resulting in increased susceptibility to bacterial infections, high levels of dietary EPA/DHA should be accompanied by low levels of dietary iron.