Tao Xue,1,* Hongbin Yu,2,* Wenming Feng,2 Yao Wang,2 Shiyong Wu,3 Lili Wang,4 Peiqin Zhu,5 Jianming Guan,6,7 Quan Sun8 1Clinical Research Center, First People’s Hospital Affiliated to Huzhou University, Huzhou, People’s Republic of China; 2Department of Hepatobiliary Surgery, First People’s Hospital Affiliated to Huzhou University, Huzhou, People’s Republic of China; 3Department of Radiology, First People’s Hospital Affiliated to Huzhou University, Huzhou, People’s Republic of China; 4Department of Nursing, Physical Examination Center of Aishan, Huzhou, People’s Republic of China; 5Department of Internal Medicine, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou, People’s Republic of China; 6Department of Ultrasound, First People’s Hospital Affiliated to Huzhou University, Huzhou, People’s Republic of China; 7Department of Ultrasound, Mingzhou Hospital, Huzhou, People’s Republic of China; 8Laboratory of Blood Transfusion Research, Huzhou Center Blood Station, Huzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quan Sun, Laboratory of Blood Transfusion Research, Huzhou Center Blood Station, Fenghuang Road 577#, Huzhou, 313000, People’s Republic of China, Email sunquanhz@163.com Jianming Guan, Department of Ultrasound, First People’s Hospital Affiliated to Huzhou University, Guangchanghou Road 158#, Huzhou, 313000, People’s Republic of China, Email guan9300@126.comBackground: The presence of macrovascular invasion (MVI) is associated with poor prognosis in advanced hepatocellular carcinoma (HCC). This study aims to evaluate the efficacy and safety of Cinobufacini therapy via hepatic arterial infusion (HAI) in advanced HCC patients with MVI.Methods: The clinical records of 130 consecutive patients with unresectable advanced HCC and MVI who had received Cinobufacini or cisplatin plus 5-fluorouracil (CF) treatment via HAI were retrospectively analyzed. The therapeutic efficacy, overall survival (OS), progression-free survival (PFS), and adverse events were compared between the two treatment groups.Results: The Cinobufacini group demonstrated significant curative effects on treatment via HAI compared with the CF group, including the objective response rate (44.9% vs 27.9%, P=0.048), the median OS (14.8 months vs 11.1 months, P=0.010), and the median PFS (10.3 months vs 6.0 months, P=0.006). Result in subgroup analysis of portal vein invasion grade supported the efficacy in Cinobufacini treatment, especially in the median OS of Vp1-2 (18.3 months vs 14.3 months, P=0.043) and Vp3 (15.0 months vs 11.4 months, P=0.046), as well as the median PFS of Vp1-2 (14.8 months vs 10.2 months, P=0.028) and Vp3 (10.8 months vs 6.6 months, P=0.033) compared with CF treatment. Cox proportional hazards model and forest plot analysis of factors confirmed the survival benefit from HAI with Cinobufacini over CF (hazard ratio [HR], 0.61; 95% CI: 0.40– 0.91; P=0.010). Multivariable analysis identified portal vein invasion grade (Vp4; HR, 1.78; 95% CI: 1.03– 2.16; P=0.032) and AFP (> 1000; HR, 1.61; 95% CI: 1.08– 1.91; P=0.039) as the independent factors for prognosis. Moreover, the total incidence of adverse events in the Cinobufacini group was significantly lower than in the CF group (60.9% vs 82.0%, P=0.009).Conclusion: Cinobufacini therapy via HAI is a viable strategy for curing advanced HCC with MVI, due to prolonged survival and a superior safety profile.Keywords: hepatocellular carcinoma, macrovascular invasion, cinobufacini, hepatic arterial infusion, efficacy