Background Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic porto - systemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. Methods We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients). Results During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant diferences were observed between the two treatment groups with respect to serious adverse events. Conclusions In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with signif icant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)