Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Presently, targeted therapyvia monoclonal antibodies to specific tumor-associated antigens is being continuously developed. Hep88 mAb hasproven to exert tumoricidal effects on the HepG2 cell via a paraptosis-like morphology. To verify the pathway, wethen demonstrated downstream up-regulation of caspase-3, caspase-8 and caspase-9, assessingmRNA expressionby real-time PCR and associated enzyme activity by colorimetric assay. Active caspase-3 determination wasalso accomplished by flow cytometry. Active caspase-3 expression was increased by Hep88 mAb treatment in adose-and time-dependent manner. All of the results indicated that Hep88 mAb induced programmed cell deathin the HepG2 cell line from paraptosis-like to apoptosis by downstream induction of caspases. These conclusionsimply that Hep88mAb might be a promising tool for the effective treatment of HCC in the future.