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This study investigates Cystobasidium benthicum (Cb) probiotic yeast and Cyrtocarpa edulis (Ce) fruit dietary effects, single (0.5 %) or combined (Cb:Ce, 0.25:0.25 %), on growth performance, humoral immunity in serum and skin mucus, and intestinal morphology of Nile tilapia (Oreochromis niloticus) after 14 and 28 days. The Cb group presented the highest (P < 0.05) specific growth rate, weight gain, and absolute growth rate with respect to the control group. Immunological assays indicated that Cb, Ce and Cb:Ce groups increased serum nitric oxide concentration compared to the control group (P < 0.05). Cb and Cb:Ce groups showed the highest serum myeloperoxidase enzyme activity at day 14 and 28, respectively (P < 0.05); whereas, Cb:Ce group had the highest (P < 0.05) myeloperoxidase activity in skin mucus. The superoxide dismutase enzyme activity was unaffected. On day 28, Cb, Ce, and Cb:Ce groups showed higher and lower (P < 0.05) catalase enzyme activity in serum and skin mucus, respectively, compared with the control group. Only the Cb group had higher (P < 0.05) total protein concentration in serum (day 14) and skin mucus (day 14 and 28) with respect to the control group. The lysozyme activity in serum (day 28) and skin mucus (day 14) was higher (P < 0.05) in the Cb group compared to the control group. Only the skin mucus of Ce group showed bactericidal activity against Aeromonas dhakensis (P < 0.05). Histological studies indicated that Cb and Cb:Ce groups increased microvilli height, and Cb, Ce and Cb:Ce augmented goblet cell area at day 14 compared to the control group (P < 0.05). At day 28, microvilli height was higher in all groups and the number of intraepithelial leukocytes increased in Cb and Ce groups with respect to the control group (P < 0.05). The ex vivo assay revealed that A. dhakensis in leukocytes decreased cell viability similar to the control group (P < 0.05). A principal component analysis (PCA) confirmed the results. In conclusion, C. benthicum in the diet was the best supplement to improve the growth and immunity of Nile tilapia., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)