Ultrastructural alterations in the liver of the snake-headed fish (Channa punctatus) following short-term exposure to 0.05 and 0.1 mg/liter of Cu were investigated by means of transmission electron microscopy. The changes consisted of extensive proliferation of the smooth endoplasmic reticulum and dilation of the rough endoplasmic reticulum, suggesting an active detoxification attempt by the liver. Mitochondrial degenerative changes such as loss of normal material density, cristae, or outer or inner membranes with mitochondrial swelling were also observed after Cu intoxication. An increase in the numbers of lysosomes and electron dense bodies was examined. Granular chromatin and electron dense accumulation were observed in the nucleus at 0.05 mg/liter of Cu after 4 days of exposure. Cytoplasmic debris in the hepatocyte cells became a frequent finding after 7 days of 0.05 mg/liter Cu treatment. More prominent alterations in hepatocytes were recorded at 0.1 mg/liter of Cu after 4 and 7 days of exposure. A highly dilated endoplasmic reticulum and shortened and reduced mitochondria were the prominent features of acute Cu toxicity. Nuclei of the necrotic cells showed marked clumping of chromatin with the aggregation of interchromatin material at the center of the nucleus. In some hepatocytes, bilobed nuclei with dilated nuclear membranes were also observed. The nucleoplasm of many cells showed continuity with the cytoplasm due to loss of nuclear inner and outer membranes. A comparison of liver pathology with that of other fish species and mammals has been attempted. The relationship of these cellular changes with the possible mode of action of Cu at cellular and subcellular levels is discussed.