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Introduction: Hand-foot-skin reaction (HFSR) is the most common side effect of multi-tyrosine kinase inhibitor therapy for unresectable hepatocellular carcinoma (uHCC). Sarcopenia has been reported to be a poor prognostic factor for HCC. Here, we performed a randomized controlled trial (RCT) of the efficacy of a β-hydroxy-β-methyl butyrate/L-arginine/L-glutamine (HMB/Arg/Gln) beverage and locomotion training as supportive care in the treatment of uHCC with lenvatinib., Methods: A total of 20 patients were enrolled from the jRCTs031190252 trial in this pilot study. HFSR was the primary endpoint, and other adverse events and skeletal muscle index at the third lumbar level (L3-SMI) were secondary endpoints., Results: Twelve patients had albumin-bilirubin grade 1, and eight had grade 2. No difference in HFSR was observed. Although interesting differences were observed in the secondary endpoints, a slight retention of L3-SMI values in the intervention group compared with that in the control group was observed(96.5% vs. 89.9%, p=0.407)., Conclusion: Although the HMB/Arg/Gln beverage and locomotion training did not reduce adverse events caused by lenvatinib, they might be useful in maintaining skeletal muscle mass. Further validation studies with a larger number of patients are warranted., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)