¼ 51, 41%), yttrium-90 radioembolization (n ¼ 17, 13%), percutaneous thermal ablation (n ¼ 41, 33%), and combination TACE/ ablation (n ¼ 15, 12%). Baseline Barcelona Clinic Liver Cancer (BCLC) stage was 0/A (n ¼ 48, 38%), B (n ¼ 33, 26%), C (n ¼ 27, 22%), and D (n ¼ 16, 13%). Histological Edmondson-Steiner (ES) grade was correlated with baseline imaging, clinical features, and radiologic response by mRECIST using binary regression models. Time-to-progression (TTP) and transplant-free survival (TFS) were compared by ES grade using Cox proportional hazard models. Results: Tumors were ES grade 1 (n ¼ 13, 10%), 2 (n ¼ 94, 76%), or 3 (n ¼ 16, 13%). Compared to low ES grades (1/2), high ES grade (3) was associated with serum AFP>50 ng/ml (OR 4.62 95% CI 1.53-13.97; P ¼ 0.007), advanced BCLC stage (OR 4.54 95% CI 1.26-16.38; P ¼ 0.02), tumor diameter >5 cm (OR 3.12 95% CI 1.08-9.01; P ¼ 0.04), and infiltrative phenotype (OR 4.98, 95% CI 1.53-16.19; P ¼ 0.008). Serum AFP, advanced BCLC stage, and tumor diameter were associated with reduced TTP and survival (P<0.05). High ES grade was not associated with differences in objective response (OR 2.47 95% CI 0.73-8.36; P ¼ 0.15), TTP (HR 1.45 95% CI 0.68-3.08; P ¼ 0.34), or TFS (HR 0.97 95% CI 0.34-2.75; P ¼ 0.95) compared to low ES grade when stratified by type of LRT. Conclusions: Poor histologic differentiation is associated with aggressive tumor features but does not provide independent prognostic information when adjusting for LRT modality. These results support deferral of biopsy of HCC diagnosed by imaging criteria prior to LRT.