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This study was carried out to evaluate the potential antibacterial and immunomodulatory effects of the dietry propionic acid when given alone or in combination with oxytetracyclines on Nile Tilapia. Apparently healthy O.niloticus (n=120, weight=62± 2.90 g) were grown in glass aquaria and were divided into the following 8 groups (15 fish per group): group 1 (G1): non-infected, un-treated control; G2: infected non treated; G3: infected treated with PA; G4: infected treated with OTC; G5: infected treated with PA + OTC; G6: non-infected treated with PA; G7: non-infected treated with OTC; G8: non-infected treated with PA + OTC. Bacterial infection occurred by intraperitoneally injection of A. hydrophila (0.5x106 CFU/ 0.02 ml PBS/fish). PA (200 mg/kg diet) and OTC (500 mg/kg diet) were given after 24 h of experimental infection. All treatment continued for 2 weeks. Among the eight groups, PA + OTC group showed the best immunomodulatory effect as noticed by a significant (p 0.05) increase in total serum protein, globulin, IgM, hematological parameters and significant (p 0.05) up regulation in the expression levels of immunity-related gene and metabolic gene (MHC I and CYP 2E1).