Background: In systemic therapy for unresectable HCC, atezolizumab plus bevacizumab is recommended as first-line, and there are no established strategies after the immunotherapy. Lenvatinib (LEN) showed a high radiological response rate both in clinical trials and real-world practice, while it was reported that age and ALBI grade 2 were associated with the discontinuation of LEN. The aim of this study is to investigate the best candidates for LEN therapy by using clinical variables. Methods: A total of 104 patients who received LEN at our institution between Apr 2018 and Feb 2021 was enrolled. The risk factors associated with overall survival (OS) and progression-free survival (PFS) were analyzed by a Cox proportional hazard model. Results: The median observation period was 12.8 months, and the median duration of LEN was 4.5 months. The median age was 74 years, and 90 patients were Child-Pugh A. BCLC stage B patients were 43%, and median AFP was 172 ng/mL. The median OS and PFS were 17.9 and 6.2 months. In this study, 72 patients received LEN as the first line. In a multivariate analysis of first-line patients, ECOG PS≥1, modified ALBI 2b or 3, AFP≥400 ng/mL, the existence of major vascular invasion (MVI), and neutrophil to lymphocyte ratio (NLR)≥2.8 were significant risk factors associated with OS and PFS. The median OS in patients with 0-1 risk factor (n = 33) was significantly longer than the patients with 2-5 risk factors (n = 39) (22.3 vs. 16.7 months, p <.0001). The median PFS in patients with no risk factor (n = 10) was 13.8 months, while the median PFS was 4.8 months in the patients with ≥2 risk factors. Among 28 patients without MVI and treated with LEN as second or later line, the median OS of the patients with 0-2 risk factors was significantly longer than those with 3-4 risk factors (21.7 vs. 7.7 months p = 0.0008). The median PFS in patients with 0-1 risk factor was 14.7 months, even though they had an experience of systemic therapy. Conclusions: LEN is strongly recommended to the patients with ECOG PS0, modified ALBI 1 or 2a, AFP < 400ng/mL, no MVI, and low NLR (< 2.8). When the patients would fulfill all these conditions, the median OS and PFS is over 20 and 12 months, both in patients with and without experience of systemic therapy.