Abstract: Objective To compare the efficacy and safety of raltitrexed and epirubicin in the treatment of unresectable primary liver cancer(PLC)patients with transarterial chemoembolization(TACE). Methods Totally 114 unresectable PLC patients with TACE were randomly divided into raltitrexed group(n=58)and epirubicin group(n=56). Both groups were treated with TACE for 2 to 5 cycles. The patients in the raltitrexed group were treated with raltitrexed and oxaliplatin, and those in the epirubicin group were treated with epirubicin and oxaliplatin. The clinical efficacy, change of alpha fetoprotein(AFP), long-term efficacy, adverse reactions and influencing factors of prognosis were compared between the two groups. Results Patients in both groups completed 2 times of TACE treatment. The objective effective rate and disease control rate of raltitrexed group were higher than those of epirubicin group(P>0.05). At four weeks after 2 times of TACE, the decreased AFP - level was observed in 24 cases in the raltitrexed group and 19 cases in the epirubicin group, and there was no significant difference between the two groups(P>0.05). At 6, 12 and 24 months of follow-up, there were no significant differences in survival rates between the two groups(P>0.05). At 18 months of follow-up, the survival rate of the raltitrexed group was significantly higher than that of the epirubicin group(P<0.05). The median progression free survival of the raltitrexed group was 12 months(95%CI: 10.76 to 13.26), which showed no significant difference when compared to 9 months of the epirubicin group(95%CI: 8.32 to 9.88)(P>0.05). The median total survival of the raltitrexed group was 18 months(95%CI: 16.85 to 19.15), which showed no significant difference when compared to 16 months of the epirubicin group(95%CI: 15.20 to 16.80)(P>0.05). The incidence of adverse reactions in the raltitrexed group was significantly lower than that in the epirubicin group(P<0.05 or P<0.01). The levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in the raltitrexed group were significantly lower than those in the epirubicin group(P<0.01). The analysis in influencing factors of prognosis showed that the female patients and those with clinical features such as hepatitis B, grade B of Child-Pugh classification, 2 points of Eastern Cancer Collaboration Group(ECOG), multiple tumors, sum of tumor long diameters greater than 8 cm, portal vein tumor thrombus, phase IIIa of TNM classification, and preoperative AFP level over 400 μg/mL were able to achieve longer median survival by raltitrexed than epirubicin(P<0.05 or P<0.01). Conclusion Compared with epirubicin, raltitrexed has a better clinical efficiency in treatment of unresectable PLC patients with TACE, which can cause less adverse reactions and achieve a longer median survival.