Background: Taurochenodeoxycholic acid (TCDCA), but not glycochenodeoxycholic acid (GCDCA) activates a phosphatidylinositol 3-kinase (PI3-K)-mediated survival pathway in vitro. Here, the effects of PI3-K inhibition on TCDCA- and GCDCA-induced hepatocellular injury, apoptosis and bile secretion were examined in the intact liver. Experimental procedures: In isolated perfused rat livers, bile flow was determined gravimetrically. Hepatovenous lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) efflux as markers of liver integrity and biliary secretion of 2,4-dinitrophenyl-S-glutathione (DNP-GS) were determined photometrically. Apoptosis was assessed by immunohistochemistry of active caspase-3 and cytokeratin 18 in liver tissue. Phosphorylation of protein kinase B (PKB/Akt) as a readout of PI3-K activity was determined by immunoblot analysis. Bile acid concentrations were determined by gas chromatography. Results: TCDCA (25 µmol/l) induced moderate liver injury by hepatocellular apoptosis and distinctly reduced bile flow and DNP-GS secretion. In contrast, GCDCA (25 µmol/l) induced severe liver injury by extensive hepatocyte apoptosis. TCDCA strongly activated PI3-K whereas GCDCA did not markedly affect PI3-K activity. Inhibition of PI3-K by 100 nmol/l wortmannin enhanced TCDCA-induced liver injury and apoptosis and tended to aggravate the cholestatic effect of TCDCA. In contrast, wortmannin reduced GCDCA-induced liver injury and apoptosis. Bile acid uptake tended to be reduced by wortmannin. The cholestatic effect of GCDCA was aggravated by wortmannin. Conclusions: Inhibition of PI3-K markedly aggravated TCDCA-induced, but not GCDCA-induced liver damage and hepatocyte apoptosis. Thus, TCDCA appears to block its inherent toxicity by a PI3-K-dependent survival pathway in the intact liver.