This study aims to clarify the role of heme oxygenase-1 (HO-1) in small-for-size liver transplantation. Transplantation was performed using 40% small-for-size or 100% whole liver grafts in rats. When no treatment was given, over-expression of HO-1 was detected predominantly in the small-for-size grafts at 6 hours after reperfusion as compared to whole grafts in both syngeneic and allogeneic combinations. Recombinant adenoviral vector encoding HO-1 gene (AdHO-1) administered to donors 48 hours before transplantation enhanced HO-1 expression in both whole and small-for-size allografts, with a predominant augmentation in the small-for-size allografts, suggesting favorable conditions for the induction of HO-1 expression in small-for-size allografts. In close relation to the expression level of HO-1, AdHO-1 significantly prolonged both whole and small-for size allograft survivals, with a remarkable effect in the small-for-size allograft group. The prolongation of allograft survival was blocked by the HO-1 inhibitor (zinc protoprophyrin IX). The non-treated small-for-size allografts demonstrated impaired liver function during the early period after reperfusion, which could be improved by over-expression of HO-1, but reversed by the HO-1 inhibitor. The markedly increase expression HO-1 in small-for-size allografts was associated with lower levels of adhesion molecules and pro-inflammatory cytokines in the early phase after reperfusion. These findings support the beneficial effects of HO-1 on allograft survival. In conclusion, the ability of small-for-size grafts in the induction of HO-1 expression might facilitate their own survival in liver transplantation.