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Since transporter interaction has been implicated as a mechanism underlying drug\u2010mediated hepatotoxicity and drug\u2013drug interactions, the interaction of PI with the hepatic canalicular efflux transporter ABCC2 (MRP2; multidrug resistance associated protein\u20102) was studied. Interaction with ABCC2\/Abcc2 was evaluated in human and rat sandwich\u2010cultured hepatocytes using 5(6)\u2010carboxy\u20102\u2032,7\u2032\u2010dichlorofluorescein (CDF) as substrate. In rat hepatocytes, interaction with estradiol\u201017\u2010\u03b2\u2010<jats:sc>D<\/jats:sc>\u2010glucuronide (E17G) efflux was also studied. In human hepatocytes, saquinavir, ritonavir and atazanavir were the most efficient inhibitors of ABCC2\u2010mediated biliary excretion of CDF, whereas in rat hepatocytes indinavir, lopinavir and nelfinavir were the most efficient. No species\u2010similarity was found for ABCC2\/Abcc2 inhibition. In rat hepatocytes, the effects on Abcc2 were substrate\u2010dependent as inhibition of biliary excretion of E17G was most pronounced for saquinavir (completely blocked), amprenavir (82% inhibition) and indinavir (68% inhibition). In conclusion, several HIV PI showed substantial ABCC2 inhibition, which, combined with the effects of PI on other hepatobiliary disposition mechanisms, will determine the clinical relevance of these<jats:italic>in vitro<\/jats:italic>interaction data. 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