Background: In the Phase III REFLECT trial, lenvatinib was superior to sorafenib in progression-free survival (PFS), time to progression, and objective response rate (ORR). This trial aimed to assess the efficacy of lenvatinib to achieve conversion surgery for initially unresectable hepatocellular carcinoma (HCC). Methods: In this multicenter prospective single-arm trial, not only technically unresectable cases but also oncologically unresectable cases were included. The oncologically unresectable cases, i.e., technically resectable but with poor prognosis, were defined as cases with macroscopic vascular invasion and/or extrahepatic metastasis. Patients eligible for the present study were treated with lenvatinib. Dynamic CT or MRI was performed every 4 weeks. After 8 weeks of lenvatinib therapy (protocol therapy), the patients were assessed for resectability, and tumor resection was performed after off of lenvatinib for 1 week or more if the tumor was considered resectable. The primary end point of the trial was the resection rate. The secondary end points were curative resection rate, overall survival time (OS), ORR, PFS, ICG retention rate at 15 minutes after lenvatinib therapy, and the resection rate after completion of protocol therapy. The trial is registered with the Japan Registry of Clinical Trials (s031190057). Results: Between July 2019 and January 2021, 49 patients from 11 centers were enrolled in this trial. One patient who died because of an accidental trauma immediately after study enrollment was excluded. The complete response (CR) and partial response (PR) rate of the 48 patients were 0% and 13% based on RECIST and 2% and 35% based on mRECIST, respectively. An R0, R1, and R2 resection was performed in 27 (56%), 2 (4%), and 4 patients (8%), respectively. Among the 15 unresected cases, the reasons for not undergoing surgery were inadequate response to lenvatinib in 10 patients (21%), decline of performance status in 2 patients (4%), refusal of surgery in 2 patients (4%), and worsening of comorbidities in 1 patient (2%). Postoperative 90-day mortality was not observed in any patients. Complications ≥grade III according to the Clavien-Dindo classification included bile leakage in 4 patients (8%) and intra-abdominal abscess in 3 patients (6%). The 1-year OS rate was 75.9%. Conclusions: This trial, which was the first prospective trial assessing conversion surgery, demonstrated the feasibility of conversion surgery after lenvatinib therapy in patients with initially unresectable HCC. The response rate of lenvatinib was similar to that of the REFLECT trial. Postoperative complications directly related to the administration of lenvatinib were not observed, suggesting the safety of preoperative lenvatinib therapy. Clinical trial information: jRCTs031190057.