A yeast was isolated from hypersaline sediments, grown and phylogenetically characterized as Sterigmatomyces halophilus strainN16. The dietary administration of this yeast was studied for its effect on skin mucosal immune and antioxidant status of gilthead seabream (Sparus aurata L.). Fish were fed a commercial diet (control, non-supplemented diet), or the same commercial diet supplemented with 0.55% or 1.1% of yeast for 15 and 30 days. One month after the end of the trial, fish from all treatments were intraperitoneally injected with pathogenic Vibrio parahaemolyticus and further fed with the same diets for one week, after which fish were also sampled. Significant increases were observed in the immune activities determined in the fish fed the yeast supplemented diets compared with the values recorded in mucus of fish from the control group. The expression levels of trypsin (one of the main digestive enzymes) and several immune-related genes (IL-1β, TNF-α, IgM, C3 and lysozyme) were also evaluated by real-time PCR in intestine and skin. Interestingly, trypsin gene expression in intestine was up regulated in both experimental diets compared with the control group, particularly in fish fed with 0.55% of S. halophilus at any time of the experimental trial. Immune-related genes in intestine and skin were strongly expressed principally in fish fed with 0.55% of S. halophilus for 15 days and 1.1% for 30 days and after infection, respectively. The present results suggest that the yeast S. halophilus can be considered as a novel fish immunostimulant. The excellent potential of marine microorganisms isolated from extreme environments with beneficial properties for fish is discussed.