On the basis of light microscopic studies, drug reactions involving the liver have been classified as hepatitic, cholestatic, and toxic. 1 The last is the result of administration of poisons affecting all species and all indi viduals in a clear dose related fashion and with a distinctive morphologic picture. These chemicals, usually organic solvents best exemplified by carbon tetrachloride, have been widely used in experimental models of hepatic injury. However, most drug reactions in the liver occur infre quently, are not clearly dose related, and mimic other diseases of the liver and biliary tract, particularly viral hepatitis and extrahepatic biliary obstruction, as far as clinical, laboratory, and morphologic features are concerned. In an effort to effect a separation of drug-induced hepatic injury from other diseases, liver biopsy specimens were examined electronmicroscopically. Cholestasis following drug administration was found to be associated with changes of bile canaliculi, whereas hepatitis-like reactions seemed to primarily alter endoplasmic reticulum. 2 · 3 Many drug reactions with cholestasis were accompanied by bile canalicular dilatation and microvillar loss and shortening. 2 · 4 · 5 However, similar changes were also found in extrahepatic biliary obstruction, 69 in viral hepatitis, 2 and in liver disease in alcoholic persons. 10 Therefore, the canalicular changes failed to provide a means of differential diagnosis of the causes of cholestasis, particularly hepatic disease versus biliary tract obstruction. The electronmicroscopic studies did indicate that short term administration of drugs such as norethandrolone, known to produce cholestasis in some persons, and retention of Bromsulphalein in most persons 11 · 12 caused canalicular dilatation even in the absence of jaundice, and the same find ings were noted in rats given the drug. 6 In rats, however, the light micro scopic hallmark of cholestasis, namely bile thrombi, are not seen. In addition to electronmicroscopic changes in bile canaliculi, the enzyme histochemical reactions of the bile canaliculi were altered.