Until now, the multiple biological effects of ionizing radiation on liver have been reported. However, there has not been any reports of fast neutron-mediated liver injuries including liver regeneration or fibrosis. Here, we described the biological effects of acute fast neutron irradiation on the liver. After the fast neutron irradiation of 0, 0.25, 1, 2, 4 and 8 Gy on mice, hepatocyte necrosis and a decrease in the total number of hepatocytes were induced dose-dependently. Binucleated hepatocytes and PCNA positive hepatocytes increased significantly at 0.25 and 1 Gy, but decreased markedly at 2, 4 and 8 Gy. The expression of cytochrome P450 2E1 (CYP2E1) showed a dose-dependent increase after fast neutron irradiation. The activation of p-Smad2/3, signaling intermediates of transforming growth factor-beta (TGF-beta), increased in hepatocytes after exposure of 0.25, 1, and 2 Gy of fast neutrons, but it was not detected in hepatic stellate cells (HSCs). In conclusion, fast neutron-induced liver damages, likely loss of hepatocytes, necrotic foci and vacuolar changes, were note on the dose dependent manner and hepatocellular regeneration were significantly diminished at doses of 2, 4 and 8Gy in a dose-dependent manner. These alterations may at least in part be associated with dose-dependent increase in CYP2E1 and p-Smad2/3. These results show promise as an approach for the treatment of fast neutrons on liver tumors and in the study of pathogenesis regarding the fast neutron-irradiated damages of the liver.