PURPOSE: We aimed to evaluate exposure-toxicity/efficacy relationship of lenvatinib by determining its target trough concentration for patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective, observational study, 28 HCC patients who had been treated with lenvatinib were enrolled between August 2018 and April 2020. We evaluated the association between the trough lenvatinib concentration and occurrence of grade ≥ 3 toxicities. Additionally, we estimated the association of the trough lenvatinib concentration with responder status (disease control; complete response, partial response, or stable disease), and progression-free survival (PFS). RESULTS: The mean trough lenvatinib concentration was significantly higher in the group with grade ≥ 3 toxicity (n = 15) than in the group with grade ≤ 2 toxicity (n = 13). Based on the receiver operating characteristic curve, the threshold values of the trough lenvatinib concentrations for predicting grade ≥ 3 toxicities and responder status were 71.4 ng/mL [area under the curve (AUC) 0.86, 95% confidence interval (CI) 0.71-1.00; p < 0.05] and 36.8 ng/mL (AUC 0.95, 95% CI 0.85-1.00; p < 0.05), respectively. Lenvatinib concentrations of 36.8-71.4 ng/mL resulted in longer PFS than concentrations < 36.8 ng/mL and ≥ 71.4 ng /mL [median 13.3 months (36.8-71.4 ng/mL) vs. 3.5 months (< 36.8 ng/mL) and 7.8 months (≥ 71.4 ng /mL), respectively]. CONCLUSIONS: Considering these results, we propose that the target trough concentration of lenvatinib could be 36.8-71.4 ng/mL for maintaining disease control status and reducing grade ≥ 3 toxicity in the treatment of HCC.