Ultrastructural changes in rat liver were studied 1, 2, 4, 6, 8, and 10 hr after administration of a single, high dose of Cd (3.9 mg Cd/kg, iv) or after repeated administration of a lower dose (0.5 mg Cd/kg, sc, 6 days/week for 6 months). These dosing regimens have been previously shown to produce hepatotoxicity and result in large accumulations of Cd in liver. In addition to light and electron microscopy, plasma enzyme activities indicative of liver injury, namely alanine (ALT) and aspartate (AST) aminotransferase, were determined at the aforementioned times. One hour after an acute dose of Cd, electron photomicrographs of liver showed dilation of the rough endoplasmic reticulum with concomitant loss of membrane-associated ribosomes, nucleolar condensation, and an increase in the number of perichromatin granules. At later times (4 and 6 hr), ultrastructural changes included mitochondrial swelling associated with matrical inclusions, further dilation and vesiculation of rough endoplasmic reticulum, and presence of a fibrillar material within cytoplasm. In contrast to changes observed after single administration of Cd, the predominant hepatic lesions in rats injected repeatedly with the metal over 6 months were interstitial fibrosis, nuclear enlargement, and an increase in number and predominance of nucleoli. Ultrastructural evidence of nuclear alterations included condensation of nucleoli and an increase in the number of perichromatin granules. These results indicate that Cd interferes with hepatic protein synthesis early after injection of a large dose, and that further degenerative changes occur later and possibly in response to protein inhibition. Although severe degenerative changes in liver were not evident in rats chronically exposed to the metal, Cd-induced changes in nuclei and nucleoli also indicate the likelihood of altered protein synthesis.