This study attempts to describe the effects of innate immune response and disease resistant of schizophyllan in orange-sported grouper, "Epinephelus coioides". The schizophyllan is a beta-glucan, and is an extraction from Schizophyllum commune fermentation. Study performed on the innate immune response showed that oral ingestion of schizophyllan at 1.0 g and 2.0 g per kilogram diets of feed levels after 7 days may significantly enhance the lysozyme activity, phagocytic activity, phagocytic index and respiration burst of the experimental groupers. Observation on the experimental challenge of pathogen showed that uses of 1.0 g and 2.0 g schizophyllan per kilogram diets in feed 14 days could significantly enhance the protection of grouper against "Vibrio alginolyticus". In this study, schizophyllan have been orally administered in grouper showing immunomodulation. Schizophyllan is an immunomodulatory of grouper, even if fed over-dosage, does not lead to over-regulation of the innate immune response.