The mechanisms accounting for the atrophy of the portal blood-deprived liver lobes after portal branch ligation (PBL) are still unclear. The first aim of this study was to confirm the role of apoptosis in this process and to determine which apoptotic pathways are involved. The second aim of the study was to evaluate the effect of blocking compensatory hyperplasia of the nonligated lobes with retrorsine on the mechanisms of apoptosis in the ligated lobes. Mitochondrial Bax, Bcl-2 and Bcl-X(L), cytosolic cytochrome c, caspase-3, -8 and -9 activities and TNF-alpha levels were assessed in the liver of rats before and at various time points, ranging from 30 min to 7 days, after PBL. Caspase activities were also measured in rats pretreated with retrorsine. Both the mitochondrial and the death receptor-mediated pathways are activated in the ligated liver lobes after portal branch ligation. Caspase activation is inhibited by retrorsine pretreatment, resulting in fewer apoptotic bodies. Apoptosis accounts for the atrophy of the ligated lobes after PBL. It is inhibited by retrorsine, suggesting an attempt to reduce the loss of liver mass when hyperplasia of the nonligated lobes is impaired