The hepatotoxicity of tunicamycin was studied in 8 to 10-week-old guinea pigs. Acute hepatic damage was produced consistently in guinea pigs given a single dose of 400 micrograms/kg of tunicamycin and observed at intervals up to 72 h post-injection. Significant elevations occurred in serum levels of liver enzymes and ammonia, while concentrations of serum proteins were lowered. A periportal pattern of hepatocellular damage, with death of many hepatocytes, was consistently observed by 72 h. Severe vacuolation of hepatocytes resulted from lipid accumulation and dilatation of cisternae of rough endoplasmic reticulum, and bile ductule hyperplasia was also observed. Swollen hepatocyte cytoplasm protruded into many hepatic blood vessels, and detached portions of hepatocytes produced emboli in pulmonary and cerebral capillaries, thus contributing to capillary occlusion in the brains of treated guinea pigs.