Objectives To evaluate the prognostic potential of Lipiodol distribution for the pharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE). Methods This prospective clinical trial ( ClinicalTrials.gov : NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016–10/2018) using 50 mg DOX/10 mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations ( C max ) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment ( n  = 10), ≥ 2 segments ( n  = 10), and lobar cTACE ( n  = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3–4 weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher’s exact test, and Pearson correlation. Results Hepatocellular ( n  = 26), cholangiocarcinoma ( n  = 1), and neuroendocrine metastases ( n  = 3) were included. Stratified according to Lipiodol distribution, DOX- C max increased from 1 segment (DOX- C max , 83.94 ± 75.09 ng/mL; DN-DOX- C max , 2.67 ± 2.02 ng/mL/mg) to ≥ 2 segments (DOX- C max , 139.66 ± 117.73 ng/mL; DN-DOX- C max , 3.68 ± 4.20 ng/mL/mg) to lobar distribution (DOX- C max , 334.35 ± 215.18 ng/mL; DN-DOX- C max , 7.11 ± 4.24 ng/mL/mg; p  = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX ( p  = 0.023) and DOXOL ( p  = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX- C max were high ETV ( p  = 0.047) and Child-Pugh B ( p  = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE. Conclusions This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX- C max and tumor response after cTACE in liver cancer. Key Points • Prospective pharmacokinetic analysis after conventional TACE revealed Lipiodol distribution (1 vs. ≥ 2 segments vs. lobar) as an imaging marker predictive of doxorubicin peak concentrations (C max ). • Child-Pugh B class and tumor hypervascularization, measurable as enhancing tumor volume (ETV) at baseline, were identified as additional predictors for higher dose-normalized doxorubicin C max after conventional TACE. • ETV at baseline and tumoral Lipiodol coverage can serve as predictors of volumetric tumor response after conventional TACE according to quantitative European Association for the Study of the Liver (qEASL) criteria.