Acute toxicity and sub-acute effects of Derristrifoliata leaves extract on histological andultrastructural alteration of Nile tilapia Oreochromisniloticus liver were studied. The experiments wereperformed under laboratory conditions with staticrenewal test-type. The fish were investigated forgrowth (indicated by length and weight), relative liverweight index, histological and ultrastructuralalteration of liver during 5 months. The median lethal concentration (96-h LC(,50))for acute toxicity was 1.99 mg/L. Base on this value, asub-acute concentration for this study was calculatedto 0.02 mg/L. From light microscopic study, thehistological changes of hepatic tissue comprised ofswelling, vacuolation and fat droplets accumulation inhepatocytes, hemorrhagic inflammation, macrophageinvasion, fibrosis, foci and diffused necrosis.Histochemical studies indicated that the treated liverwere less in glycogen storage but much more lipidaccumulation than control groups. The ultrastructuralalterations of hepatocyte consisted of mitochondrialcontraction and/or swelling, proliferation andfragmentation of RER, shifting of RER to SER,increasing of secondary Iysosome. Hepatic cell injuriesand liver tissue lesions were increased along thecontinuous exposure of 5 months experimental period.Hence, these cellular changes were time dependenteffect. Additionally, a significant (p(<,-)0.5)reduction in growth was observed in 3rd month tilled5th month of treated groups. The relative liver weightindex was also significant (p(<,-)0.5) increased in the4th month of experiment.