PURPOSE:To prospectively investigate whether Lipiodol can be used as a potential imaging biomarker of tumor response after conventional transarterial chemoembolization (cTACE) for both primary and secondary liver cancer. MATERIALS AND METHODS: This prospective single-center single-arm clinical trial enrolled a total of 39 patients with primary or secondary liver malignancy [hepatocellular carcinoma (HCC), n = 22 and non-HCC, n = 17]. Patients were treated with cTACE according to a standardized protocol and underwent multimodality imaging at baseline [magnetic resonance imaging (MRI)/computed tomography (CT)/positron emission tomography (PET)]; at 24 hours post-TACE (CT); and at 30, 90, and 180 days post-TACE (MRI/CT/PET). Image data analysis included quantitative assessment of tumor characteristics, Lipiodol deposition, fluorodeoxyglucose uptake, and tumor response assessment. Statistical analysis included linear regression, Student's t tests, Wilcoxon rank sum and signed rank test, Chi-square, and Fisher's exact test. RESULTS: Image analysis demonstrated that baseline tumor diameter (R2 = 0.4, P = .0001), area (R2 = 0.45, P < .0001), volume (R2 = 0.3, P < .002), and enhancing volume (cm3, R2 = 0.23, P < .002) at baseline correlated inversely with Lipiodol tumor coverage and response rates. Baseline tumor enhancement in % of the total tumor was the only parameter to positively correlate with Lipiodol coverage (R2 = 0.189, P = .0456). Patients with high Lipiodol coverage of the tumors showed a higher tumor quantitative European Association for the Study of the Liver response rate at 30-day follow-up (P = .004). Lipiodol retention in both primary and secondary liver tumors was sustained over time, while nontarget hepatic deposits demonstrated near-complete elimination at 30-day follow-up (P < .001). CONCLUSION: Lipiodol deposition in liver tumors can be predicted using quantitative baseline imaging characteristics and correlates with tumor response. This supports another role for Lipiodol, namely, that of an imaging biomarker of tumor response after cTACE.