BACKGROUND The multikinase inhibitor sorafenib inhibits angiogenesis and tumor cell proliferation. Sorafenib targets signaling pathways involved in liver regeneration. Previous works on regenerating mouse liver show differing results. We asked to which degree different lengths of sorafenib treatment would influence liver regeneration after hepatic resection in rats. METHODS Fischer-344 rats received intragastric injections of sorafenib (5-15 mg/kg/d), underwent a two-thirds partial hepatectomy (PH), and were sacrificed at different time points thereafter. Sorafenib treatment was stopped 0, 3, or 14 d after PH. Serum levels of aminotransferases and labeling indices of S-phase nuclei (bromodeoxyuridine and MIB-5) were analyzed, body and liver weights measured, and levels of phospho-ERK determined by Western blot. RESULTS Sorafenib increased aminotransferases and the number of S-phase nuclei at baseline, but decreased liver weights and levels of phospho-ERK 24 h after PH. The number of S-phase nuclei and mitotic indices decreased 48 h after PH and increased 7 d after PH in animals on sorafenib treatment. Relative liver weights were restored 5 d after PH in control rats, at 7 d in animals receiving sorafenib prior to surgery, at 10 d in rats where sorafenib was stopped 3 d after surgery, and after 14 d in rats on continuous treatment. CONCLUSIONS In this rat model, the regenerating liver adapted to the proliferation-inhibitory effect of sorafenib during continuous treatment. Sorafenib given after hepatic resection did not completely inhibit liver regeneration, but it prolonged the regenerative phase in proportion to the length of treatment.