Purpose: The disintegration of heme produces carbon monoxide (CO), a known vasodilator, which is catalyzed by heme oxygenase (HO). This study aimed to clarify the effect of HO inhibition on septicrat livers using two types of HO inhibitors; Sn-protoporphyrin (Sn-PP) and Zn-protoporphyrin (Zn-PP). Methods: Sepsis was induced in male Sprague-Dawley rats by cecal ligation and puncture (CLP). Either NaOH or HO inhibitors were injected intraperitoneally; first 18h prior to CLP, then immediately after CLP. The animals were killed 12 and 24h after CLP and the liver tissue and plasma were harvested. Results: Using Northern blotting, we found that mRNA of the stress-inducible isozyme, HO-1, was dramatically induced 12h after CLP. Administering the HO inhibitors, Sn-PP and Zn-PP (5mol/kg), induced a significant inhibition of the elevation of aspartate aminotransferase plasma levels, the elevation of cyclic guanosine monophosphete (cGMP) in the liver tissue, and the increase in the sinusoidal space ratio, 24h after CLP. Both Sn-PP and Zn-PP decreased the mortality rate 24h after CLP compared with normal saline. Conclusions: CO produced by excessively induced HO-1 after CLP promotes an immoderate dilation of the sinusoidal space through the up-regulation of cGMP, resulting in liver dysfunction. Therefore, administering HO inhibitors at appropriate doses could be beneficial for the amelioration of sepsis-induced liver dysfunction.