PURPOSE: To determine comprehensive treatment parameters predictive of complete pathologic necrosis (CPN) in early-stage hepatocellular carcinoma (HCC) treated with glass microsphere radiation segmentectomy (RS). METHODS: This study is a secondary analysis of 61 tumors with available post-treatment imaging from a previously published cohort treated with RS using Yttrium-90-containing glass microspheres prior to liver transplantation. Post-treatment Bremsstrahlung SPECT-CT single-compartment, multi-compartment, and voxel-based dosimetry analyses were performed using dose confirmation software and compared between tumors that achieved CPN vs. non-CPN. RESULTS: Median specific activity (SA [1242 vs. 867 Bq, p = 0.018]), total angiosome dose (577 vs. 352 Gy, p = 0.005) tumor dose (1086 vs. 738 Gy, p = 0.007), and angiosome hepatic parenchymal dose (490 vs. 309 Gy, p = 0.005) were higher in the CPN (n = 43) vs. non-CPN (n = 18) cohort. Receiver operating characteristic (ROC) curve analyses (area under the curve [AUC], sensitivity, specificity) demonstrated that a SA ≥ 570 Bq (0.69, 88%, 50%), total angiosome dose ≥ 439 Gy (0.73, 70%, 67%), tumor dose ≥ 844 Gy (0.72, 76%, 67%), and angiosome hepatic parenchymal dose ≥ 420 Gy (0.73, 60%, 78%) were predictive of CPN (p <
0.05). No statistical difference was found between the tumor or angiosome particle density (PD), tumor volume, or angiosome volumes in the CPN and non-CPN cohorts. Subgroup ROC analysis of tumors that received SA <
570 Bq (n = 15) demonstrated that a total angiosome dose ≥ 263 Gy (0.85, 83%, 89%) and tumor dose ≥ 451 Gy (0.83, 100%, 67%) and were predictive of CPN (p <
0.05). An average angiosome PD ≥ 11.4 × 10 CONCLUSION: CPN was predicted by a SA of ≥ 570 Bq, total angiosome dose of ≥ 439 Gy, tumor dose of ≥ 844 Gy, and angiosome hepatic parenchymal dose ≥ 420 Gy. A total angiosome PD of ≥ 11.4 × 10 CLINICAL TRIAL REGISTRATION: Not applicable.