The in vitro antibacterial activity of enrofloxacin and amoxycillin was evaluated against Aeromonas hyDROPhila pathogen. Also, the in vivo efficacy of both drugs was investigated on Oreochromis niloticus fish experimentally infected with Aeromonas hyDROPhadministration at their therapeutic dose levels (10 mg I kg b.wt I day) and(80 mg I kg b.wt I day) for 10 successive days, respectively. The obtained results indicated. that both enrofloxacin and amoxycillin were effective invitro and in vivo against Aeromonas hyDROPhila micro-organism withMIC of (0.012) ug/ml for enrofloxacin and (0.4) ug/ml for amoxycillin,indicating high antibacterial activity of both drugs. It was found that thenumbers of dead fish in the groups administered enrofloxacin and loramoxycillin were significantly lower than that in control group and themortality in infected group was (83.33%) while in the infected and treated groups with enrofloxacin and amoxycillin were (10%) and (16.66%)respectively. Enrofloxacin and amoxycillin residues in liver, kidney and muscles of Oreochromis niloticus were determined after administration oftheir recommended therapeutic doses orally for ten successive days. Thehighest concentration of enrofloxacin was found in kidney than liver andmuscles. Enrofloxacin residues in liver disappeared on the 1 th day, inmuscles disappeared on the 13th day while in kidney disappeared on the15th day post drug treatment.The highest concentration of amoxycillin was detected in liver thankidney and muscles. Amoxycillin residues disappeared on the 7th day post drug treatment from muscles and disappeared on the 9th day from bothliver and kidney post drug treatment.-128~