OBJECTIVE The immunotoxin of HEL-PE38KDEL has been proven to be a novel biological reagent which has specific cytotoxic effect against breast cancer cells with positive erbB-2, 3, 4. However it has not been tested the interaction of the immunotoxin and the conventional chemical anti-cancer drugs. This study was designed to investigate the mechanism of the synergistic effect between HEL beta 1-PE38KDEL and cisplatin. METHODS The tests of Annexin V binding and Western blot were performed to detect the apoptosis in the breast cancer cell lines MDA-MB-453, 2LMP, and the gastric cancer cell of N87 treated with single or drug combination. RESULTS In MDA-MB-453 and N87 with high expression of erbB-2, 3, 4, percentage of the apoptosis cell was significantly higher in the group treated with the drug combination than that in the group treated with the single drug (P < 0.01). To the contrast, in 2LMP cells with low expression of erbB-2, 3, 4, there was no difference between the drug combination and the single drug group (P > 0.05). In MDA-MB-453 and N87, degradation of PARP, caspase-3 was more in the group treated with the drug combination than that in the group treated with the drug alone. Overexpressions of bcl-2, mp53 were inhibited in the group treated by the drug combination. On the contrary overexpressions of bcl-2, mp53 were not inhibited in the group treated with the single drug. While these changes of PARP[poly (ADP)-ribose polymerase], caspase-3, mp53, bcl-2 could not be observed in the control cell line of 2LMP. CONCLUSIONS The combination of HEL beta 1-PE38KDEL and cis-platin could promote the synergistic effect on apoptosis in the target cancer cells with high expression of erbB-2, 3, 4 which might be one of the mechanism of these two drugs.