Background Little is known about factors that influence the efficacy of transarterial radioembolization (TARE). Purpose To determine the relationship between tumor radiation-absorbed dose and survival and tumor response in locally advanced inoperable hepatocellular carcinoma treated with TARE. Materials and Methods This was a secondary analysis of prospectively acquired data (between December 2011 and March 2015) from participants who received TARE in the Sorafenib versus Radioembolization in Advanced Hepatocellular Carcinoma (SARAH) trial (ClinicalTrials.gov identifier NCT01482442). Tumor-absorbed dose was computed using technetium 99m (Tc) macroaggregated human albumin (MAA) SPECT/CT. Visual agreement among CT, Tc-MAA SPECT/CT, and yttrium 90 (Y) SPECT/CT or PET/CT was scored as optimal, suboptimal, or not optimal. Overall survival (OS) and tumor response at 6-month follow-up CT (Response Evaluation Criteria in Solid Tumors, version 1.1) were assessed. OS was evaluated using Kaplan-Meier tests. A propensity score comparing participants receiving a tumor dose greater than or equal to 100 Gy (best cut-off according to the receiver operating characteristic curve and median tumor radiation-absorbed dose values in the study groups) with those receiving sorafenib was calculated. Results One hundred twenty-one participants (median age, 67 years; interquartile range [IQR] 61-73 years; 110 men) were evaluated in the dose-survival group, and 109 (median age, 66 years; IQR 61-71 years; 100 men) were evaluated in the dose-tumor response group. In the dose-survival group, median OS was 9.3 months (95% confidence interval [CI] 6.7 months, 10.7 months), and median tumor radiation-absorbed dose was 112 Gy (IQR 68-220 Gy). Participants who received at least 100 Gy (n = 67) had longer survival than those who received less than 100 Gy (median, 14.1 months [95% CI 9.6 months, 18.6 months] vs 6.1 months [95% CI 4.9 months, 6.8 months], respectively; P < .001), and those with optimal agreement (n = 24) had the longest median OS (24.9 months; 95% CI 9.6 months, 33.9 months). In the dose-tumor response group, tumor radiation-absorbed dose was higher in participants with disease control versus those with progressive disease (median, 121 Gy [IQR 86-190 Gy] vs 85 Gy [IQR 58-164 Gy]; P = .02). The highest disease control rate was observed in 31 of 40 participants (78%) with a tumor radiation-absorbed dose greater than or equal to 100 Gy and optimal agreement. Conclusion Higher tumor radiation-absorbed dose computed at technetium 99m macroaggregated human albumin SPECT/CT was associated with better overall survival and disease control in hepatocellular carcinoma treated with transarterial radioembolization with yttrium 90 in the Sorafenib versus Radioembolization in Advanced Hepatocellular Carcinoma trial. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Sofocleous and Kamarinos in this issue.