Bcl-xL is often overexpressed in human hepatocellular carcinoma cells, contributing to resistance to various chemotherapeutic agents. In this study, we investigated the role of Bcl-xL in two modes of cell death induced by different doses of doxorubicin, apoptosis and cell death through mitotic catastrophe. Bcl-xL overexpression in various hepatoma cells effectively blocked apoptosis induced by high dose doxorubicin, inhibiting the loss of mitochondrial membrane potential, release of mitochondrial cytochrome c and caspase activation. Contrastingly, Bcl-xL overexpression did not block low dose doxorubicin-induced mitotic catastrophe and subsequent non-apoptotic cell death, without affecting abnormal cell cycle progression, formation of multiple micronuclei, loss of mitochondrial membrane potential, release of mitochondrial cytochrome c, and the clonogenicity of cells exposed to low dose doxorubicin. These findings indicate that low dose doxorubicin-induced cell death through mitotic catastrophe may provide an alternative therapeutic strategy for Bcl-xL-overexpressing hepatoma cells, which are resistant to pro-apoptotic treatments.