Seaweeds may represent immunostimulants that could be used as health-promoting fish feed components thereby offering an alternative for the use of antibiotics. This study was performed to gain insights into the immunomodulatory effects of dietary seaweeds in Atlantic salmon. Specifically tested were 10% inclusion levels of Laminaria digitata (SW1) and a commercial blend of seaweeds (Oceanfeed®) (SW2) against a fishmeal based control diet (FMC). Differences between groups were assessed in growth, feed conversion ratio (FCR) and blood parameters hematocrit (Hct) and hemoglobin (Hb). After a LPS challenge of fish representing each of the three groups, RNAseq was performed on head kidneys to determine transcriptomic differences in response to the immune activation, to our knowledge for the first time in fish in this context. Atlantic salmon fed with dietary seaweeds showed slightly higher FCRs and more homogenous growth but in general no major differences in performance in comparison with fishmeal fed fish. RNAseq resulted in ~154 million reads which were mapped against a NCBI Salmo salar reference and against a de novo assembled Salmo salar reference for analyses of expression of immune genes and ontology of immune processes among the 87,600 cDNA contigs. The dietary seaweeds provoked a more efficient immune response which involved more efficient identification of the infection site, and processing and presentation of antigens. More specifically, chemotaxis and the chemokine-mediated signaling pathway with involvement of genes such as C-C motif chemokine 19 were improved and the defense response to Gram-positive bacterium reduced. The predicted integrin alpha-2-like gene had by far the highest up-regulated expression and may therefore represent a key marker gene of the LPS immune response in salmonids. Specific Laminaria digita effects included reduction of the cytokine-mediated signalling pathway as indicated by the cytokine macrophage migration inhibitory factor, and interferon-gamma-mediated signalling as indicated by STAT1 and the gamma-interferon-inducible lysosomal thiol reductase precursor. Highly upregulated and specific for this diet was the expression of Major histocompatibility complex class I-related gene protein. The commercial blend of seaweeds caused more differential expression than Laminaria digita and improved immune processes such as receptor-mediated endocytosis, inflammatory response, cell adhesion and response to lipopolysaccharide. Particularly expression of many important immune receptors was up-regulated illustrating increased responsiveness. NF-kappa-B inhibitor alpha is an important gene that marked the difference between both seaweed diets as Laminaria digita inhibits the production of this cytokine while the blend of seaweeds stimulates it. It can be concluded that replacing fishmeal partly with seaweeds such as Laminaria digita can have important modulatory effects on the immune capacity of Atlantic salmon resulting in a more efficient immune response. Overall design: Deep-sequencing transcriptome analysis of head kidney samples derived from LPS-challenged Salmo salar specimens after a 42-day seaweed or control diet: Laminaria digitata (Seaweed 1 (SW1) n=3), Oceanfeed (Seaweed 2 (SW2) n=3), fishmeal-based control diet (FMC n=3).