The effects of hepatotoxic doses of acetaminophen and furosemide on the function and composition of hepatic endoplasmic reticulum were compared from 3 to 24 h after administration. Acetaminophen caused a significant decrease in microsomal protein concentration as early as 3 h after its administration, but furosemide did not affect the microsomal protein concentration until 24 h after the dose. Both acetaminophen and furosemide decreased the concentrations of cytochrome P-450 and cytochrome b5 in microsomes, and the activity of microsomal ethylmorphine N-demethylase and aniline hydroxylase. Glucose-6-phosphatase and UDP-glucuronyl transferase were not significantly affected by acetaminophen or furosemide administration, and neither diene conjugation nor hepatic triglycerides were increased. Incorporation of 3H-L-leucine into liver proteins was decreased by 50% after the administration of either acetaminophen or furosemide.