Houttuynia cordata Thunb (HCT) is a native herb found in Southeast Asia which features variouspharmacological activities against allergy, inflammation, viral and bacterial infection, and cancer. The aims ofthis study were to determine the cytotoxic effect of 6 fractions obtained from silica gel column chromatographyof alcoholic HCT extract on human leukemic Molt-4 cells and demonstrate mechanisms of cell death. Six HCTfractions were cytotoxic to human lymphoblastic leukemic Molt-4 cells in a dose-dependent manner by MTTassay, fraction 4 exerting the greatest effects. Treatment with IC50 of HCT fraction 4 significantly induced Molt-4apoptosis detected by annexinV-FITC/propidium iodide for externalization of phosphatidylserine to the outerlayer of cell membrane. The mitochondrial transmembrane potential was reduced in HCT fraction 4-treatedMolt-4 cells. Moreover, decreased expression of Bcl-xl and increased levels of Smac/Diablo, Bax and GRP78proteins were noted on immunoblotting. In conclusion, HCT fraction 4 induces Molt-4 apoptosis cell throughan endoplasmic reticulum stress pathway.