The use of ethanol is common among the cocaine-abusing population. Both of these agents have been associated with hepatotoxicity. This investigation employed an in vitro model to study cocaine and ethanol interactions in the liver. Hepatocytes (2 x 10(6) cells/ml) isolated from male Sprague-Dawley rats were exposed to saline, cocaine, ethanol or the combination of cocaine and ethanol. Cell membrane damage in hepatocytes was assessed by the uptake of 0.4% trypan blue and the leakage of the enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) into the incubation media. An increase in trypan blue uptake was observed following exposure to 5 mm cocaine as early as 30 min of incubation. Hepatocytes were unaffected by treatment with 25 and 50 mm ethanol for the 2-hr time period studied. Including ethanol in incubations containing 1 or 5 mm cocaine did not result in any additional toxicity when compared with hepatocytes treated with cocaine alone. However, AST leakage from hepatocytes exposed to cocaine in combination with ethanol was decreased when compared with hepatocytes treated with cocaine alone. These findings suggest that exposing hepatocytes simultaneously to cocaine in combination with ethanol, under the conditions of this experiment, does not enhance the hepatocellular toxicity produced by cocaine alone.