Purpose: To investigate the clinical efficacy and safety of combination therapy of hepatic arterial infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) therapy in the treatment of advanced hepatocellular carcinoma (HCC).Methods: In this retrospective clinical research, from March 2018 to December 2019, 1158 HCC patients categorized as BCLC stage C were reviewed for eligibility. We utilized propensity score matching (PSM) to mitigate initial disparities between the groups. The evaluation of the best tumor response was conducted in accordance with mRECIST 1.1 criteria. The difference in survival outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between groups were compared.Results: Following the eligibility review, 453 patients underwent a combined treatment of HAIC with PD1 inhibitors (HAIC-PD1 group), while 221 patients received HAIC monotherapy (HAIC group) met the inclusion criteria and were finally enrolled in this study. In the entire cohort, the HAIC-PD1 group exhibited significantly prolonged overall survival (median overall survival: 40.4 months vs. 9.7 months, p < 0.001) and progression-free survival (median progression-free survival: 22.1 months vs. 5.8 months, p < 0.001). By propensity score, patients were matched according to baseline differences, resulting in all 442 patients in group HAIC-PD1 (n = 221) and group HAIC (n = 221). After PSM adjustment, as well, the survival of the HAIC-PD1 group was still distinctly longer than the HAIC group (median overall survival time, 40.4 months vs 9.7 months, p < 0.001; median progression-free survival, 22.1 months vs 5.7 months, p < 0.001). Univariate and multivariable analysis demonstrated that AFP level, metastasis, and therapeutic schedule were independent predictive factors for overall survival.Conclusion: The combination therapy of HAIC and PD1 inhibitors successfully extended OS to advanced HCC patients and could be a better choice than HAIC monotherapy.