Rats were maintained for 2 years on diets supplying 0.1, 0.01, and 0.001 μg of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)/kg/day. Analysis of these diets indicated 2200, 210, and 22 parts per trillion (ppt) of TCDD. Ingestion of 0.1 μg/kg/day caused an increased incidence of hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue, whereas a reduced incidence of tumors of the pituitary, uterus, mammary glands, pancreas, and adrenal gland was noted. Other indications of toxicity at this dose level included increased mortality, decreased weight gain, slight depression of erythroid parameters, increased urinary excretion of porphyrins and δ-aminolevulinic acid, along with increased serum activities of alkaline phosphatase, γ-glutamyl transferase and glutamic-pyruvic transaminase. Gross and histopathologic changes were noted in the hepatic, lymphoid, respiratory, and vascular tissues. The primary hepatic ultrastructural change at this high dose level was proliferation of the rough endoplasmic reticulum. Terminal liver and fat samples from rats at this high dose level contained 24,000 and 8100 ppt of TCDD, respectively. Rats given 0.01 μg/kg/day for 2 years had a lesser degree of toxicity than that seen at the highest dose level. This included increased urinary excretion of porphyrins in females, liver lesions (including hepatocellular nodules), and lung lesions (including focal alveolar hyperplasia). Terminal liver and fat samples from rats of this dose level contained 5100 and 1700 ppt of TCDD, respectively. Ingestion of 0.001 μg of TCDD/kg/day (∼22 ppt in the diet) caused no effects considered to be of any toxicologic significance. At this lower dose level, terminal liver and fat samples each contained 540 ppt of TCDD. These data indicate that continuous doses of TCDD sufficient to induce severe toxicity increased the incidence of some types of tumors, while reducing other types. During the 2-year study in rats, no increase in tumors occurred in those rats receiving sufficient TCDD to induce slight or no manifestations of toxicity.