Background: Optimal administration of transarterial chemoembolization (TACE), the standard approach for intermediate-stage hepatocellular carcinoma (HCC), requires clinical and technical expertise. We sought to evaluate whether TACE retains its effectiveness when administered across a broad range of health care settings. Furthermore, as the use of yttrium90 (Y90) radioembolization has been increasing, we explored the comparative effectiveness of Y90 as an alternative to TACE. Methods: Patients with HCC diagnosed from 2004 through 2009 treated initially with TACE or Y90 were identified from the SEER-Medicare linkage. Key covariates included prediagnosis α-fetoprotein (AFP) screening, complications of cirrhosis, and tumor extent. Effect of treatment, patient, and health care system factors on overall survival (OS) was evaluated using multivariable Cox proportional hazards. Stratified OS estimates are provided. Propensity score (PS) weighting was used to compare effectiveness of Y90 with TACE. Results: Of 1528 patients who underwent intra-arterial embolization, 577 received concurrent chemotherapy (eg, TACE). Median OS was 21 months (95% CI, 18–23) following TACE and 9 months (95% CI, 1–41) following Y90. Refined survival estimates stratified by stage, AFP screening, and liver comorbidity are presented. The 90-day mortality rate after TACE was 21% to 25% in patients with extrahepatic spread or vascular invasion. In the PS-weighted analysis, Y90 was associated with inferior survival, with an adjusted hazard ratio of 1.39 (95% CI, 1.02–1.90). Conclusions: The effectiveness of TACE is generalizable to Medicare patients receiving care in a variety of treatment settings. However, early posttreatment mortality is high in patients with advanced disease. We found no evidence of improved outcomes with Y90 compared with TACE. Survival estimates from this large cohort can be used to provide prognostic information to patients considering palliative TACE.