NIK-333 (an acyclic retinoid) has been reported to prevent recurrence of hepatocellular carcinoma (HCC) in patients after curative treatment. This study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLT) and pharmacokinetics of NIK-333 administrated p.o. at doses ranging 300-900 mg/day. Patients who were cancer-free after percutaneous local ablation or surgical resection of HCC were enrolled. The total daily dose was administrated as a single dose (single-dose stage) followed by a week of rest, and then in two equally divided doses administrated after breakfast and supper for 48 consecutive weeks (repeated-dose stage). No patients at the dose levels of 300 mg/day and 600 mg/day developed any DLT. At the final dose level of 900 mg/day, three of the nine patients developed grade 3 hypertension as a DLT. There were no significant difference values of maximum drug concentration (C(max) ) and log(C(max) ) between fasting and postprandial condition. In the repeated-dose stage, there was no significant difference between the start and week 24 of NIK-333 administration within any dose cohort in either the mean area under the blood concentration time curve (0-6 h) or the C(max) . NIK-333 was well-tolerated when administrated p.o. at doses of up to 600 mg/day for 48 weeks. Hypertension was noted as a DLT at the dose level of 900 mg/day, and this dose was considered to be inappropriate. The recommended dose for the phase II/III clinical trial is thought to be 300 mg/day and 600 mg/day. © 2011 The Japan Society of Hepatology.