The morphologic changes induced by subcutaneous injection of varying doses of thallium acetate in adult male and female Sprague-Dawley rats were studied with the light and electron microscopes. The animals were sacrificed at various intervals within the period of 18 hours to 6 1 2 months after the initial injection. With the light microscope, renal eosinophilic casts, enteritis, and severe colitis were consistently present in the acutely poisoned animals. In the subacutely poisoned animals, frequent foci of perivascular cuffing and a rare focus of recent necrosis were seen in the brain. No changes were noted with the light microscope in the chronically poisoned animals. With the electron microscope, the most consistent changes in all groups of poisoned animals were noted in the kidney, liver, and intestine. In the kidney there was swelling of the tubule cells and partial to total loss of microvilli in many of the swollen cells. In swollen cells of the proximal tubules, the endoplasmic reticulum was dilated and partially ruptured. Intraluminal tubular casts of membranous debris and cytoplasmic organelles were frequently seen in all portions of the renal tubules. Greatly increased numbers of autophagic vacuoles, lysosomes, lipid droplets, and residual bodies were present in tubular cells, particularly in the proximal convoluted tubules. Degenerative changes were frequently present in the mitochondria of the kidney, liver, and intestine; they were sometimes also observed in the brain, seminal vesicle, and pancreas. These changes included swelling of mitochondria and partial or total loss of cristae and mitochondrial granules, increased size and density of mitochondrial granules with occasional electron-lucent cores within these granules, and increased numbers and stacking of mitochondrial cristae. In hepatocytes of subacutely and chronically poisoned animals, there were infrequent accumulations of homogeneous electron-opaque material in the center of mitochondria, with a peripheral displacement of the enlarged and aggregated mitochondrial granules. Autophagic vacuoles and lysosomes were found in increased numbers in all organs examined. Lipid, in the form of droplets, was often increased in hepatocytes of the chronically poisoned animals. No intranuclear or cytoplasmic inclusion bodies were seen. The variety of changes noted in mitochondria and the increased numbers of autophagic vacuoles and lipid droplets in thallium poisoning are not considered specific for thallium, and are similar to changes seen following cellular injury evoked by a variety of agents. The enlargement of mitochondrial granules is thought to be due to the accumulation of thallium within these structures. It is proposed that one mode of action of thallium may be to combine with mitochondrial sulfhydryl groups and thereby interfere with oxidative phosphorylation.