We investigated the mechanism underlying the effect of a combination treatment of I radioactive seed implantation and lobaplatin (LBP) in hepatocellular carcinoma. The effects of administration of HCC cells and subcutaneous tumor model of mice with different doses of I or a sensitizing concentration of LBP alone， or in combination， on cellular apoptosis and proliferation were analyzed and it was confirmed that LBP promotes I-induced apoptosis and inhibition of proliferation of HCC. Furthermore， isobaric tag for relative and absolute quantification labeling analyses suggested that I promoted the apoptosis and inhibition of proliferation of HCC cells by upregulating the expression of PERK-eIF2α-ATF4-CHOP pathway， a well-known apoptosis-related pathway. Moreover， LBP was found to boost the I-induced upregulation of this pathway and increase the apoptosis. Our data indicate that LBP promotes the apoptotic and anti-proliferative effects of I and provide a firm foundation for better clinical application of this combination therapy.