The present study was carried out at Mariculture Research Center, Arish University, North Sinai, Egypt. This study aimed to examine the effects of total replacement of fish meal by a combination of prebiotic   mixtures and protease enzyme on growth performance and feed utilization parameters of red tilapia. A total of 150 fish were equally distributed in 15 glass aquaria. Ten fingerlings per aquarium were stocked with an average initial weight 7.40±0.05g and an average initial length 7.30±0.24cm. The fish were acclimatized for two weeks at experimental condition. This study was conducted as four treatments with three replicates. The fish were fed a diet containing 30.14±0.08% crude protein and isocaloric 443.11±0.5Kcal/kg twice a day at a rate of 3% of total body weight for 84 days. At the end of experiment body weight, length and whole body composition were calculated to determine growth parameters and feed utilization. There were significant difference P≤0.05 for all results between treatments. The results of growth parameters indicated that T4 was recorded the highest values of most growth parameters. But T3 recorded the highest condition factor. FCR and PER were not significantly differences between all treatments. The highest feed and protein intake were recorded for control group and T4. The highest dry matter and ether extract of whole body composition were recorded for T3. But the best protein value, gross energy, protein and energy retained were recorded for T4. There were no significantly differences P>0.05 at fat and ash retained.