AIM: To investigate the efficacy and safety of TACE combined with lenvatinib and PD-1 inhitibors for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).METHODS: HCC patients with PVTT who received TACE combined with lenvatinib and PD-1 inhitibors as first-line therapy in clinical practice were included in this study retrospectively. Therapeutic outcomes of this regimen were calculated based on the target lesions evaluated using mRECIST criteria. Additionally, all the subjects were followed up regularly to obtain the prognostic outcomes. Safety profile observed during the combination therapy was collected and documented specifically. Log-rank test was used for exploratory analysis between prognosis and baseline characteristics, and Cox regression analysis was adopted for multivariate analysis. RESULTS: A total of 67 HCC patients with PVTT who received TACE combined with lenvatinib and PD-1 inhitibors were included in this study ultimately, 4 patients achieved complete response, 30 patients were partial response, 25 patients were stable disease, 5 patients were disease progression and 3 patients were not available for the response outcomes. Therefore, the objective response rate (ORR) of this regimen was 50.7% and disease control rate (DCR) was 88.1%. Prognostic data suggested that the median progression free survival (PFS) of the 67 HCC patients with PVTT was 9.3 months (95%CI: 5.85-12.75), and the median overall survival (OS) was 24.4 months (95%CI: 19.11-29.69). Safety profile highlighted that a total of 65 patients experienced adverse reactions regardless of grade when received TACE combined with lenvatinib and PD-1 inhitibors (97.0%), among whom, a total of 34 patients were deemed as grade ≥3 adverse reactions (50.7%). The most common adverse reactions were hypertension, fatigue, abnormal liver function, nausea and vomiting and diarrhea. CONCLUSION: TACE combined with lenvatinib and PD-1 inhitibors as first-line therapy for HCC with PVTT demonstrated encouraging efficacy and acceptable safety profile.