Background: Symptomatic portal hypertension (SPH) leads to a poor prognosis as a common complication in advanced hepatocellular carcinoma (HCC) patients due to cirrhosis or portal vein tumor thrombus. Although combined therapy including Lenvatinib and PD-1 inhibitors has shown valuable advantages in advanced HCC, the above strategy is limited by liver function impairment due to SPH complications such as variceal bleeding and refractory ascites. Transjugular intrahepatic portosystemic shunt (TIPS) directly relieves portal hypertension which may create a chance for advanced HCC patients with SPH to receive systemic therapy. Thus, TIPS plus following Lenvatinib and PD-1 inhibitor may serve as an effective anticancer modality. This study aimed to evaluate the efficacy and safety of TIPS combined with Lenvatinib and PD-1 inhibitor for advanced HCC patients with SPH. Methods: This retrospective study included thirteen advanced HCC with SPH patients who received TIPS combined with Lenvatinib and PD-1 inhibitor (Tislelizumab/Sintilimab) between January 2020 and January 2023. Main inclusion criteria: a confirmed HCC (BCLC stage C) based on the AASLD with either pathological or imaging findings; no previous systemic anticancer treatment; Child-Pugh score ≤10; ECOG status: 0-1. Portal hypertension with complications (variceal bleeding, refractory ascites). The outcome measures included objective response rate (ORR) (assessed with mRECIST v1.1), disease control rates (DCR), progression-free survival (PFS), overall survival (OS), SPH recurrence rate, and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: With a median follow-up of 6.5 months (range 2.3-19.0), 13 patients with a median age of 57 years (range: 33-70) were evaluable for response and toxicity. 3 (23.1%) patients with Tislelizumab and 10 (76.9%) with Sintilimab. 7 (53.8%) patients were classified as Child-Pugh A class. According to mRECIST v1.1, ORR was 38.5% (95%CI, 11.8%-61.6%) with 1CR and 4 PR, and the DCR was 53.8% (95%CI, 21.3%-73.4%). The median overall survival (OS) was 16.5 months (95%CI,16.1-17.0). The prevalence of rebleeding, ascites and hepatic encephalopathy, was 7.7 %, 15.4%, and 7.7%, respectively. Treatment-related adverse events were confined to grades 1-2 occurring in 3/13 (23.1%) patients as rash (2, 15.4%) and fatigue (1, 7.7%). There were no treatment-related serious adverse events. Conclusions: TIPS combined with Lenvatinib and PD-1 inhibitor demonstrated a valuable anti-cancer strategy for advanced HCC patients with SPH based on the low recurrence rate of SPH and acceptable side effects.