This study was carried out to evaluate the response of Nile tilapia, Oreochromis niloticus to acute copper toxicity. Nile tilapia fingerlings (2.97 g/f ± 0.37) were acclimated and randomly distributed at a rate of 10 fish per 60-L aquarium. In a series of static renewal-toxicity tests, fish were exposed to concentrations of 0, 5, 10, 15, 20, 25, 30, 35 and 40 mg L-1 copper sulfate (CuSO4·5H2O). Fish not exposed to any chemical served as negative controls. Histological sections were done in fish gills and liver in all treatments. Estimates of mean 96-h LC50 values (median lethal concentration) value of copper sulfate was 31.2 mg L-1 (7.94 mg copper L-1). In all exposure groups, some of the typical gill lesions are presented. The main alternations observed after the exposure to the cupper were epithelial hyperplasia, lifting of the lamellar epithelium, edema in the filamental epithelium, Curling, clubbed tips of secondary lamella and finally a complete fusion of several secondary lamellae at the 35 mg CuSO4 concentration. The severity of the lesions detected increased with the increase of copper sulfate concentration. Exposure to concentrations of copper sulfate more than 10 mg L-1 increased the arithmetic thickness of secondary lamella epithelium in O. niloticus which was significantly higher (P<0.001) than the corresponding control. However, the liver of the Cu-treated fish showed histological alternations such as cytoplasmic rarefaction, an increase of cytoplasmic vacuolation, decreasing the number of hepatocytes nucleus in hepatic tissue and nuclear pyknosis.