Objective To explore the clinical efficacy of lienal polypeptide injection combined with transcatheter arterial chemoembolization (TACE) for treatment of patients with advanced primary liver cancer. Methods A total of 60 patients with advanced primary liver cancer were enrolled from Jun. 2013 to Jan. 2015 in Eastern Hepatobiliary Surgery Hospital, and were divided randomly into treatment group (lienal polypeptide injection combined with TACE, n=30) and control group (TACE, n=30). We observed the quality of life (KPS score) and immunity index of the patients in two groups before treatment and observed the clinical efficacy (RECIST 1.1 criteria), KPS score and immunity index after treatment for one month, then and recorded and compared the adverse effects and survival rates in two groups. Results The objective effective rate (complete remission and partial remission) was 63.3% (19/30) in treatment group and was 33.3% (10/30) in control group, with significant difference between the two groups (P<0.05). The KPS score of treatment group was better than that of control group (P<0.05). In treatment group, the CD3⁺ and CD4⁺ lymphocytes and the ratio of CD4⁺ to CD8⁺ lymphocytes were significantly increased after the treatment (P<0.05), and they had no significant change in control group before and after treatment. The incidences of adverse reactions, such as hematological toxicity and gastrointestinal reactions in treatment group were significantly lower than those in the control group (P<0.05). There was no significant difference in one-year survival rate between treatment group (53.3%) and control group (43.3%, P>0.05), while the two-year survival rate of treatment group was significantly higher than that in the control group (40.0% vs 13.3%, P<0.05). Conclusion Lienal polypeptide injection combined with TACE can improve the clinical efficacy and survival rate of the patients with advanced primary liver cancer.