PURPOSE: To investigate hepatocellular carcinoma tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative Y-single-photon emission computed tomography (SPECT)/computed tomography (CT) after Y-radioembilization with glass microspheres. We also investigated the relationship between normal liver D and toxicities. METHODS AND MATERIALS: Y-radioembolization activity distributions for 34 patients were based on quantitative Y-bremsstrahlung SPECT/CT. D maps were generated using a local-deposition algorithm. Contrast-enhanced CT or magnetic resonance imaging scans of the liver were registered to Y-SPECT/CT, and all tumors larger than 2.5 cm diameter (53 tumors) were segmented. Tumor mean D and BED (Dmean and BEDmean) and dose volume coverage from 0% to 100% in 10% steps (D0-D100 and BED0-BED100) were extracted. Tumor response was evaluated on follow-up using World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST (mRECIST) criteria. Differences in dose metrics for responders and nonresponders were assessed using the Mann-Whitney U test. A univariate logistic regression model was used to determine tumor dose metrics that correlated with tumor response. Correlations among tumor size, tumor Dmean, and tumor dose heterogeneity (defined as the coefficient of variation) were assessed. RESULTS: The objective response rates were 14 of 53, 15 of 53, and 30 of 53 for WHO, RECIST, and mRECIST criteria, respectively. WHO and RECIST response statuses did not correlate with D or BED. For mRECIST responders and nonresponders, D and BED were significantly different for Dmean, D20 to D80, BEDmean, and BED0 to BED80. Threshold doses (and the 95% confidence interval) for 50% probability of mRECIST response (D) were 160 Gy (123-196 Gy) for Dmean and 214 Gy (146-280 Gy) for BEDmean. Tumor dose heterogeneity significantly correlated with tumor volume. No statistically significant association between Dmean to normal liver and complications related to bilirubin, albumin, or ascites was observed. CONCLUSIONS: Hepatocellular carcinoma tumor dose-response curves after Y-radioembolization with glass microspheres showed Dmean of 160 Gy and BEDmean of 214 Gy for D with a positive predictive value of ∼70% and a negative predictive value of ∼62%. No complications were observed in our patient cohort for normal liver Dmean less than 44 Gy.