Background: Most patients (pts) with hepatocellular carcinomas (HCC) are diagnosed at intermediate to advanced stages, at which they have missed the opportunity for curative resection. Combining a PD-1 inhibitor with tyrosine kinase inhibitors (TKIs)has achieved a high response rate for advanced HCC in first- and second-line settings. This study aimed to explore the efficacy and safety of conversion therapy with sintilimab (PD-1 inhibitor) plus Lenvatinib (TKI) in pts with unresectable locally intermediate advanced HCC. Methods: This was a phase 2, single-arm study (NCT04042805). Eligible pts were adults who were newly diagnosed with HCC, not amenable to curative resection, no extrahepatic metastasis, with an ECOG PS 0-1 and Child-Pugh class A/B. Pts received 12mg or 8mg oral Lenvatinib daily plus 200mg intravenous sintilimab every 3 weeks until disease progression or unacceptable toxicity, followed by multidisciplinary assessment and potential hepatectomy. The primary endpoint was tumor objective response rate (ORR) RECIST version 1.1. Secondary endpoints included conversion resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between August 1, 2019, and September 1, 2021, 26 pts were enrolled with a median age of 60 years (range, 30-78). The study population was predominantly male (92%), and 92% were HBV-positive. Patients were classified as BCLC stage B (46%) and stage C (54%). Twenty-six pts were evaluable for response, with an ORR of 35% (95%CI, 0.15-0.54) and a DCR of 92% (95%CI, 0.81-0.99). Seven (27%) pts received hepatectomy, and 1 (4%) patient received radical ablation and stereotactic radiotherapy. With a median follow-up of 9 months (range, 2-24), the median PFS and OS were not reached. All pts were evaluable for toxicity, and 20 (77%) pts had at least one treatment-related AE (TRAE). TRAEs occurring in ≥20% of pts were hypothyroidism (38%), proteinuria (31%), and hypertension (23%). Five pts had grade 3 TRAEs. Conclusions: In view of the encouraging response rate observed and the acceptable safety profile, the lenvatinib plus sintilimab regimen may achieve a favorable conversion rate and be a feasible conversion therapy for patients with unresectable locally intermediate to advanced HCC. Clinical trial information: NCT04042805.