Abstract: Objective To explore the clinical efficacy and drug-toxic reactions of raltitrexed combined with oxaliplatin (RALOX protocol) and 5-fluorouracil + calciumfolinate + oxaliplatin (FOLFOX 4 protocol) in the treatment of patients with middle and advanced primary liver cancer (PLC).Methods A total of 72 patients with PLC were selected and randomly divided into RALOX group (n =34) and FOLFOX 4 group (n =38).The objective response rate (RR) was evaluated every 6 weeks after chemotherapy,while objective remission rate (OR),disease-control rate (DCR),median survival rate (mOS),median progression-free survival (mPFS),1-year survival rate (SR) as well as toxic and adverse reactions were observed.Results In RALOX group,31 patients were evaluable,with OR,DCR,mOS,mPFS,and 1-year SR being 19.4％,51.6％,7.2 months,3.4 months,and 22.6％,respectively.In FOLFOX 4 group,29 patients were evaluable,with OR,DCR,mOS,mPFS,and 1-year SR being 13.8％,48.3％,6.9 months,3.3 months and 20.7％,respectively.RALOX group was significantly lower than FOLFOX 4 group in the incidence rates of gastrointestinal reactions,liver toxicity,cardiac toxicity,peripheral nervous toxicity and hand-foot syndrome,but there were no significant differences in the incidence rates of renal toxicity and myelosuppression between two groups.Conclusion RALOX is safe and effective in the treatment of patients with middle and advanced PLC,and is superior to FOLFOX 4 protocol in clinical efficacy with mild adverse reactions.