Proteasome inhibition has recently been demonstrated to inhibit hepatic fibrogenesis in the BDL mouse by blocking stellate cell NF-B activation. The effect of proteasome inhibition on liver injury, however, is unclear. Our current aims were to assess the effect of the proteasome inhibitor, bortezomib, on liver injury in the BDL mouse. Liver injury was assessed in 7-day BDL mice treated with a single dose of bortezomib on day 4 after bile duct ligation. Despite NF-B inhibition by bortezomib, liver injury and hepatocyte apoptosis were reduced in treated BDL mice. The anti-apoptotic effect of bortezomib was likely mediated by an increase in hepatic c-FLIP levels, a potent anti-apoptotic protein. Unexpectedly, numerous mitotic hepatocytes were observed in the bortezomib treated BDL mice liver specimens. Consistent with this observation, PCNA immunoreactivity and cyclin A protein expression were also increased with bortezomib treatment. Bortezomib therapy was also associated with a decrease in numbers and activation of Kupffer cells/macrophages. In conclusion, these data suggest the proteasome inhibitor bortezomib reduces hepatocyte injury in the BDL mouse by mechanisms associated with a reduction in hepatocyte apoptosis, a decrease in Kupffer cell/macrophage number and activation, and increased hepatocyte proliferation.