Acetaminophen-induced hepatotoxicity and associated hepatic congestion were investigated by scanning and correlative transmission electron microscopy. Acetaminophen (750 mg/kg orally) causes changes in cell surface morphology and the relationship between hepatocytes and sinusoidal lining cells. There is endocytic vacuolation at lateral and sinusoidal margins of centrilobular hepatocytes, loss of microvilli, Disse space enlargement, dilation of bile canaliculi, and disappearance of the studlike projections from hepatocyte lateral surfaces. Erythrocytes enter the enlarged Disse space and endocytic vacuoles via enlarged pores in sinusoidal lining cells, thereby collapsing the sinusoids. Lining cells are not lost, but apparently held in position by preservation of intercellular junctions, cytoplasmic projections from hepatocytes, and anchorage by fat-storing cells within the Disse space. Congestion can abate by 24 hours, indicating that erythrocytes can return to the general circulation from the Disse space.