This study was conducted to evaluate the effects of dietary administration of Bacillus subtilis and fructooligosaccharides (FOS) on immune system and disease resistance of Red tilapia (Oreochromis sp.). Experiment was randomly designed with 4 treatments including control; B.subtilis 10⁷ CFU/g; B.subtilis 10⁷ CFU/g and 0,2% FOS; B.subtilis 10⁷ CFU/g and 0,5% FOS for 4 weeks, triplications for each treatment. Sampling was collected after 2 weeks, 4 weeks of feeding and after 3 days of infection with Streptococcus agalactiae. Several immune parameters including the total erythrocyte cells, leucocyte cells, each type leucocyte and lysozyme activity were observed for immune response. The result showed that the total erythrocyte cells, leukocyte cells, monocytes, neutrophils, lymphocytes and lysozyme activity were significantly increased (p B.subtilis 10⁷ CFU/g + 0,2% FOS and B.subtilis 10⁷ CFU/g + 0,5% FOS compared to those of control treatment. After infection with Streptococcus agalactiae, a cumulative mortality of fish fed B.subtilis and FOS were lower than mortality of fish in the control treatment. Moreover, mortality of fish fed B.subtilis 10⁷ CFU/g + 0,5% FOS is the lowest (26.7%) and significant difference with other treatments.