Nitroglycerin (NTG), a nitric oxide (NO) donor, has been shown to reduce portal pressure in cirrhotic patients. Using the in situ perfusion of normal and cirrhotic rat livers, we compared the vascular relaxation induced by either NTG or the spontaneous nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP). Normal and cirrhotic livers were perfused (40 mL/min, 37°C) with Krebs' solution in a recirculating system. After preconstriction with methoxamine (10−4 mol/L), a dose-response study was performed using 6 cumulative doses of NTG or SNAP (10−7 to 3 × 10−5 mol/L). NOx (NO2 + NO3) production in the perfusate was measured by chemiluminescence. Cirrhotic livers exhibited lower vasorelaxant responses, compared with normal livers, to both NTG (P < .0001) and SNAP (P = .0020). In normal livers, NTG and SNAP induced similar vasorelaxant responses (P = .44). In cirrhotic livers, NTG induced less vasorelaxation than SNAP (P < .0001). In the presence of NTG (P = .0045), but not SNAP (P = .99), NOx production in experiments with cirrhotic livers was lower than in experiments with normal livers. In conclusion, in cirrhotic rat livers, the vasorelaxant response to NTG is impaired owing to both a decreased metabolism of this NO donor and an inability of the hepatic vasculature to respond to NO.