Background: Combination therapies have been explored for the treatment of hepatocellular carcinoma (HCC) with favorable results, including PD-1 inhibitors plus lenvatinib and transarterial chemoembolization (TACE) plus lenvatinib. However, triple therapy with TACE combined with lenvatinib plus PD-1 inhibitors has not been investigated for patients with unresectable HCC. This study therefore aimed to investigate the effectiveness and safety of TACE combined with lenvatinib plus sintilimab in patients with advanced HCC. Methods: A single-arm retrospective study based on medical records and imaging data from 60 patients diagnosed with HCC using noninvasive methods or biopsy at the Cancer Hospital of the University of Chinese Academy of Sciences and the First Hospital of Medical University between January 2019 and March 2021. Eligible patients had received lenvatinib 12 mg (bodyweight >60 kg) or 8 mg (bodyweight <60 kg) orally once daily 2 weeks before TACE. Subsequently, sintilimab was administered at a dose of 200 mg intravenously on day 1 of a 21-day treatment cycle following TACE. The TACE procedure was repeated 4-6 weeks later and the chemotherapy regimens used included oxaliplatin (75 mg/m²) and iodized oil mixed with epirubicin (30-50 mg/m²). Objective response rate (ORR) and duration of response (DOR) were the primary endpoints and were assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: The analysis included data from 52 patients; 86.4% were male, 76.7% were aged ≤65 years, 13.5% and 86.5% had an ECOG performance status (PS) of 0 and 1, respectively and 88.5% and 11.5% had a Child-Pugh score of A and B, respectively. All patients were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage B (25%) or C (75%) disease. After a median follow-up of 12.5 months (95% confidence interval (CI), 9.1–14.8), the ORR was 46.7% (28/60: complete response, n=4; partial response, n=24). Twenty-three patients had stable disease, and nine had progressive disease. The median DOR for confirmed responders was 10.0 months (95% CI, 9.0–11.0). The median progression-free survival and overall survival were 13.3 months (95% CI, 11.9–14.7) and 23.6 months (95% CI, 22.2–25.0), respectively. In total, 84.6% (n=44) of patients had adverse events (AEs) of any grade. The most common treatment-related AEs were fatigue (30.8%), hypertension (25.0%), diarrhea (19.2%), decreased appetite (23.0%), and palmar-plantar erythrodysesthesia (21.1%). Conclusions: TACE combined with lenvatinib plus sintilimab is a promising and tolerable therapeutic regimen for patients with unresectable HCC.