Objective:The objective of the study was to investigate whether hepatocellular carcinoma (HCC) histology is associated with clinical and computed tomographic/magnetic resonance imaging features and locoregional therapy (LRT) outcomes. Subjects and Methods:This single-center retrospective study included 124 consecutive patients (92 men, median age 59 years) with 132 HCC diagnosed by biopsy between 2008 and 2017 before LRT. Patients underwent chemoembolization (n = 51, 41%), ablation (n = 41, 33%), yttrium-90 radioembolization (n = 17, 13%), and chemoembolization/ablation (n = 15, 12%). Barcelona clinic liver cancer (BCLC) stage was 0/A (n = 48, 38%), B (n = 33, 26%), C (n = 27, 22%), and D (n = 16, 13%). Edmondson-Steiner (ES) grade and cytology were correlated with baseline features and radiologic response using logistic regression. Time to progression (TTP) and transplant-free survival (TFS) were analyzed using Cox proportional hazard models. Results:High ES grade was associated with α-fetoprotein (AFP) >50 ng/ml (odds ratio [OR] 4.6, 95% confidence interval [CI]: 1.5-13.9; P < 0.01), tumor diameter >5 cm (OR 3.1, 95% CI: 1.1-9.0; P < 0.05), infiltrative appearance (OR 5.0, 95% CI: 1.5-16.2; P < 0.01), and BCLC Stage C (OR 4.5, 95% CI: 1.3-16.4; P = 0.02). Clear-cell subtype was associated with non-viral cirrhosis (OR 5.3, 95% CI: 1.6-17.2; P < 0.01) and atypical enhancement (OR 3.1, 95% CI: 1.0-9.3; P < 0.05). AFP, BCLC Stage B, and diameter were associated with reduced TTP and TFS (P < 0.05). Neither ES grade nor clear-cell subtype was associated with objective response (OR 2.3, 95% CI: 0.7- 7.4; P = 0.15 and OR 1.1, 95% CI: 0.4-3.4; P = 0.87, respectively), TTP (P > 0.20), or TFS (P > 0.90) on univariate or stratified analysis. Conclusion:Histologic grade is associated with aggressive tumor features, while clear-cell HCC is associated with non-viral cirrhosis and atypical enhancement. Unlike AFP, BCLC stage, and tumor size, histologic features were not associated with LRT outcomes, supporting biopsy deferral for imaging diagnosed HCC.