The pathogenesis of 1,1-dichloroethylene (1,1-DCE)-induced hepatotoxicity was investigated in fasted male rats by identifying the earliest morphological alterations in organelles. In situ perfusion-fixed liver tissue was examined by light and electron microscopy at 1, 2, or 3 hr after oral administration of 25, 50, and 100 mg 1,1-DCE/kg in mineral oil. The earliest morphological alterations, which occurred within 1 to 2 hr after 1,1-DCE administration, were dilation of bile canaliculi with an increase in the number of microvilli or membrane fragments in canaliculi and the formation of canalicular diverticuli in centrolobular hepatocytes. Subsequently, microvilli on sinusoidal surfaces were disrupted or lost. Membrane whorls were frequently found in bile canaliculi, the space of Disse, and between the lateral membranes of hepatocytes at early times. As injury progressed, centrolobular hepatocytes retracted from endothelial cells and sinusoidal plasma membranes invaginated to form cytoplasmic vacuoles. Stereological analysis of centrolobular hepatocytes at the 25 mg/kg dose showed a significant increase in canalicular volume density by 3 hr and no detectable alteration in mitochondrial volume density. These results indicate that changes in canalicular shape and microvilli configuration are the earliest morphological alterations following 1-DCE ingestion.