The major concern of living donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be developed. To investigate the protective effect of somatostatin related to hemodynamic stress on small-for-size liver graft injury, we applied a treatment regimen of low-dose somatostatin in a rat orthotopic liver transplantation model using small-for-size grafts (median, 38.7%; range, 35–42%). Somatostatin was given at 5 minutes before total hepatectomy and immediately after reperfusion in the recipient (20 μg/kg). Graft survival, portal hemodynamics, intragraft gene expression and hepatic ultrastructural changes were compared between the rats with or without somatostatin treatment. Seven-day graft survival rates in the somatostatin treatment group were significantly improved compared to the control group (66.7% vs. 16.7%, P = 0.036). In the treatment group, portal pressure and hepatic surface blood flow were significantly decreased within the first 30 minutes after reperfusion, whereas in the control group, transient portal hypertension and excessive hepatic blood flow were observed. Intragraft expression (both messenger RNA and protein) of endothelin-1 was significantly downregulated accompanied with upregulation of heme oxygenase-1 and A20. Better preservation of liver function was found in the treatment group. Hepatic ultrastructure, especially the integrity of sinusoids, was well protected in the treatment group. In conclusion, low-dose somatostatin rescues small-for-size grafts from acute phase injury in liver transplantation by attenuation of acute-phase shear stress that resulted from transient portal hypertension. Liver Transpl 12:621–627, 2006. © 2006 AASLD.