The present study is designed to investigate the Pro-bac, a commercial probiotic as an immunostimulant, growth promoter and antibacterial, for African Sharptooth Catfish, Clarias gariepinus. The immuno-potentiation effects of Pro-bac probiotic were investigated after 30 successive days of dietary supplementation of catfish. Seventy-two apparently healthy catfish with average body weight of 50 ± 5g were used. Twenty-four fish were used to investigate some biochemical and immune parameters. In addition, forty-eight fish were used as challenge test with virulent Aeromonas hydrophila strain to evaluate the ability of fish received the feeding additives to resist diseases. Histopathological exam of liver, kidney and spleen were also investigated. Our results proved that, oral supplement of probiotic stimulate the non-specific immunity at cellular and humoral levels as indicated by the enhanced lymphocytes level, increased total proteins, albumins and globulins. Moreover, kidney functions were improved in the probiotic group, which measured by the significant decreased in urea level. The level of sodium, potassium and chloride were increased significantly in probiotic group than in control diet. Besides, weight gain of catfish was significantly increased in the probiotic group than in the basic diet group. The mortality percent of fish fed with probiotic ration and subjected to infection challenge with A. hydrophila were significantly lower than those that received the basic diet. Histopathological examination showed normal histological structure of liver, kidney and spleen. The present study clearly demonstrated that Pro-bac mixture of probiotics had significant stimulating effects on the immune system and disease resistance of C. gariepinus.