Whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of portal-pressure lowering effect in advanced cirrhosis is controversial. This study aimed to evaluate the systemic and splanchnic hemodynamic effects of β-blockers in decompensated vs compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis.Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of cirrhosis decompensation (ascites with or without overt-encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting β-blockers and again after 1-to-3 months of treatment (short-term).403 patients were included, 190 decompensated and 213 compensated. At baseline, decompensated patients had higher portal-pressure than compensated patients and were more hyperdynamic, with higher Cardiac-Output (CO) and lower arterial-pressure. Under β-blockers, decompensated patients had lower portal-pressure decrease (10±18%vs15±12%,P<0.05) and had greater reductions in heart-rate (P<0.001) and CO (17±15%vs10±21%, P<0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with β-blockers than survivors (21±14%vs15±16%, P<0.05) and CO under β-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index=0.74, 95%CI:0.66-0.83). Death risk was higher in decompensated-patients with CO<5L/min vs CO≥5L/min (Subdistribution-Hazard-Ratio= 0.44,95% CI= 0.25 to 0.77; P= 0.004).In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to β-blockers is greater in those with decompensated cirrhosis than in compensated with higher reduction of hearth-rate and CO, while portal pressure decrease is smaller. The short-term effect of β-blockers on CO might adversely influence survival in decompensated cirrhosis, which suggests that careful dosage titration with non-invasive CO-monitoring might be helpful.