In cirrhotic patients under pharmacologic treatment for portal hypertension, a reduction in hepatic venous pressure gradient (HVPG) of >or=20% of baseline or to <or=12 mm Hg markedly reduces the risk of variceal rebleeding. This study was aimed at evaluating whether these hemodynamic targets also prevent other complications of portal hypertension and improve long-term survival. One hundred five cirrhotic patients included in prospective trials for the prevention of variceal rebleeding were studied. Seventy-three of the patients had 2 separate HVPG measurements, at baseline and under pharmacologic therapy with propranolol +/- isosorbide mononitrate. Patients were followed for up to 8 years. Survival and risk of developing portal hypertension-related complications were compared between responders and nonresponders. Twenty-eight patients showed a reduction of HVPG >or=20% of baseline or to <or=12 mm Hg (responders), and 45 patients were nonresponders. Nonresponders had a significantly greater risk of developing variceal rebleeding (P =.013), ascites (P =.025), spontaneous bacterial peritonitis (P =.003), hepatorenal syndrome (P =.026), and hepatic encephalopathy (P =.024) than responders. Eight-year cumulative probability of survival was significantly lower in nonresponders than in responders (52% vs. 95%, respectively, P =.003). At multivariate analysis, being a nonresponder was independently associated with the risk of developing rebleeding, ascites, spontaneous bacterial peritonitis, and lower survival. In conclusion, in cirrhotic patients receiving pharmacologic treatment for prevention of variceal rebleeding, a decrease in HVPG >or=20% or to <or=12 mm Hg is associated with a marked reduction in the long-term risk of developing complications of portal hypertension and with improved survival.