Abstract: Objective Anti-tumor cytotoxic drug is one kind of the most common drugs causing drug-induced liver injury（DILI）. This study aimed to observe and evaluate the efficacy and safety of magnesium isoglycyrrhizinate injection（MgIG）for prevention of chemotherapy-induced acute liver injury in a large-scale population with malignant tumors. Methods It was a prospective， open-label，randomized controlled and nationwide multi-center study（MAGIC-301 Study）. Patients who received the chemotherapy regimen containing one of the following four chemotherapy drugs or more，cisplatin（≥60 mg/m2），oxaliplatin（≥85 mg/m2）， cyclophosphamide（≥600 mg/m2） and gemcitabine（≥2000 mg/m2），were randomized to the MgIG group and the control group. The MgIG group was assigned to receive MgIG injection 200mg/d ivgtt one day before the start of chemotherapy and lasting for at least 5 days. The control group was assigned to receive only chemotherapy regimen without MgIG injection. Referring to National Cancer Institute-Common Terminology Criteria for Adverse Events（NCI-CTC AE） version 4.0，the occurrence of liver injury，including the incidence and severity degree， was strictly observed and compared both before and after chemotherapy. Rescue hepatoprotective treatments were administered if necessary. Results The study was carried out at 28 cancer centers in China between February 28，2013 and December 31，2015. A total of 1200 patients were enrolled into the study. Of these patients，1146（95.5%）patients were included in the full analysis set（FAS）and randomized to the MgIG group（n=766）and the control group（n=380）respectively. The baseline demographics and clinical characteristics，including age，gender，weight，history of liver disease，type of malignancy and chemotherapy regimen etc， were well balanced between the groups（P>0.05）. In the FAS， 62.63% of patients in the control group presented with liver injury after the chemotherapy， while 52.81% in the MgIG group（P=0.0004）. The analyses of NCI grading for the severity of liver injury showed that the incidence of grade 2 or more liver function abnormity was 12.37% in the control group and 10.07% in the MgIG group after the chemotherapy（P=0.0008）. In addition， 32.37% of patients presented with the elevation of liver injury grade for at least one level in the control group，which increased by 11.17% compared with the MgIG group（P<0.0001）. In the MgIG group， the incidence of the liver function abnormity decreased by 7.11%（P=0.0188），22.36% （P=0.0033） and 18.71%（P=0.0380）respectively in the different chemotherapy regimens containing platinum drugs，cyclophosphamide or gemcitabine. The incidence of alanine aminotransferase（ALT）and glutamicoxaloacetic transaminase（AST）abnormity in the MgIG group were significantly lower than those in the control group after chemotherapy. On the second week of chemotherapy（d13-d15），the incidence of ALT and AST abnormity decreased significantly in the MgIG group，which reduced by 50% compared with the control group（ALT：8.63 % vs. 16.58%，P<0.0001；AST：10.72% vs. 20.05%，P<0.0001）. During the study period， the rescue treatments were administered in 1.3% of patients in the MgIG group，while occurring in 9.2% of patients in the control group（P<0.0001）. The incidence of AE was similar between the two groups. Conclusion The study results suggest that the DILI induced by the chemotherapy containing the platinum drug，cyclophosphamide or gemcitabine was characterized by the higher incidence and the more serious hazardness. Thus，more attention should be paid，especially to enhance the surveillance of liver function in the whole course and the management of liver injury in the clinical practice. Prophylaxis with MgIG injection can significantly reduce the incidence and severity of DILI before the chemotherapy initiation and during the concurrent chemotherapy. It is worthy of investigation further and clinical application widely.