Reduced sinusoidal endothelial nitric oxide (NO) production contributes to increased intrahepatic resistance and portal hypertension after liver injury. We hypothesized that V-PYRRO/NO, an NO donor prodrug metabolized "specifically" in the liver, would reduce portal venous pressure (PVP) without affecting the systemic vasculature. Liver injury was induced in male BALB/c mice by weekly carbon tetrachloride (CCl4) gavage. PVP and mean arterial pressure (MAP) were recorded during intravenous administration of V-PYRRO/NO. In vivo microscopy was used to monitor sinusoidal diameter and flow during drug administration. Mean PVP was increased in CCl4-treated mice compared to mice undergoing sham treatment. In dose-response experiments, the minimum dose of PYRRO/NO required to acutely lower PVP by 20%, the amount believed to yield a clinically meaningful outcome, was 200 nmol/kg. This dose decreased portal pressure in both cirrhotic animals (23.4 ± 2.0%, p<0.001 vs. vehicle) and sham-treated animals (19.5± 2.3% decrease, p<0.001 vs. vehicle) by a similar magnitude. This concentration also led to dilation of hepatic sinusoids and an increase in sinusoidal volumetric flow, consistent with a reduction of intrahepatic resistance. The effect of V-PYRRO/NO on MAP was significant at all concentrations tested, including at the lowest, 30 nmol/kg (p<0.001 vs. vehicle for all doses). We conclude that V-PYRRO/NO had widespread vascular effects, and as such, is unlikely to be suitable to treat portal hypertension. As the potential of this or other similar compounds for treatment of portal hypertension is evaluated, effects on the systemic vasculature will also need to be considered.