BACKGROUND & AIMS: Idarubicin has high cytotoxicity on hepatocellular carcinoma (HCC) cells, high hepatic extraction ratio and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolization) was conducted in cirrhotic patients with HCC to estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics, and health-related quality of life. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolization. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: Fifteen patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20, and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) by modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months (95%CI 3.0-14.6 months) and median overall survival was 20.6 months (95%CI 3.7-28.7 months). Pharmacokinetic analysis of idarubicin showed an interesting profile. Health-related quality of life results confirmed the good safety results. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolization sessions. Encouraging safety, responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve responses and survival in unresectable HCC patients. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolization was well-tolerated and gave promising efficacy in terms of tumour control and survival. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.