In the present study, we used bone marrow transplanted mice and revealed the role of bone marrow derived cells in liver regeneration after partial hepatectomy (PH). Irradiated wild type (WT) mice received a bone marrow transplant from either WT, TNF (tumor necrosis factor)-alpha knockout (KO), or interleukin (IL)-6 KO donors. Both TNF-alpha KO- and IL-6 KO-transplanted mice compared with WT-transplanted mice showed decreased hepatocyte DNA synthesis after PH. TNF-alpha KO-transplanted mice showed no nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription (STAT) 3 binding after PH, while IL-6 KO-transplanted mice showed NF-kappaB, but not STAT3, binding. Lack of AP-1 or C/EBP binding or expression of c-jun or c-myc mRNA after PH was unrelated to the timing and amount of DNA replication. In conclusion, The TNF-alpha and IL-6 signals from the blood are necessary for liver regeneration and NF-kappaB and STAT3 binding are activated via TNF-alpha and IL-6 signal pathways.