A multicenter analysis was conducted to evaluate the main prognostic factors driving survival after radioembolization using yttrium‐90–labeled resin microspheres in patients with hepatocellular carcinoma at eight European centers. In total, 325 patients received a median activity of 1.6 GBq between September 2003 and December 2009, predominantly as whole‐liver (45.2%) or right‐lobe (38.5%) infusions. Typically, patients were Child‐Pugh class A (82.5%), had underlying cirrhosis (78.5%), and had good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0‐1; 87.7%), but many had multinodular disease (75.9%) invading both lobes (53.1%) and/or portal vein occlusion (13.5% branch; 9.8% main). Over half had advanced Barcelona Clinic Liver Cancer (BCLC) staging (BCLC C, 56.3%) and one‐quarter had intermediate staging (BCLC B, 26.8%). The median overall survival was 12.8 months (95% confidence interval, 10.9‐15.7), which varied significantly by disease stage (BCLC A, 24.4 months [95% CI, 18.6‐38.1 months]; BCLC B, 16.9 months [95% CI, 12.8‐22.8 months]; BCLC C, 10.0 months [95% CI, 7.7‐10.9 months]). Consistent with this finding , survival varied significantly by ECOG status, hepatic function (Child‐Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha‐fetoprotein), and presence of extrahepatic disease. When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All‐cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. Conclusion: This analysis provides robust evidence of the survival achieved with radioembolization, including those with advanced disease and few treatment options. (HEPATOLOGY 2011;)