F-180 is a new, long-acting analog of vasopressin with a selective agonist effect on the vascular V1a receptors, with the advantage of having no effect on renal V2 receptors. F-180 is approximately 20 times more powerful than terlipressin in reducing portal pressure and has less marked systemic effects. The present study investigated the effects of F-180 on the outcome of portal hypertension-related bleeding in hypovolemic rats. Partial portal vein-ligated rats were subjected to portal hypertension-related bleeding by sectioning a first-order branch of the ileocolic vein. After hemodynamic stabilization, a second sectioning of the first-order branch of the ileocolic vein section was performed in the already hypovolemic animals, and either F-180 or placebo was administered. Blood transfusion was adjusted to maintain mean arterial pressure (MAP) γ > 80 mm Hg. The first section of a first-order branch of the ileocolic vein induced a hemorrhage of similar severity in both groups of rats. After a 2nd sectioning of a first-order branch of the ileocolic vein section, F-180 was more effective than placebo in recovering shock (MAP, 21% ± 23% vs. 0% ± 13% in placebo; P < .05), preventing portal pressure (PP) increase during blood transfusion (PP: −1% ± 19% vs. 47% ± 65% in placebo; P = .07), reducing transfusion requirements (2.9 ± 3.3 mL vs. 11.2 ± 6.0 mL in placebo; P < .01), diminishing the magnitude of collected blood losses (5.1 ± 2.2 g vs. 12.7 ±7.7 g in placebo; P < .05), and decreasing the mortality from the portal hypertension-related bleeding (10% vs. 60% in placebo; P < .05). In conclusion, in hypovolemic portal-hypertensive rats during a portal hypertension-related bleeding, F-180 rapidly recovers arterial pressure and decreases transfusion requirements, blood losses, and mortality.