Arsenic compounds (As2O3 orAs4S4) have been used successfully for the treatment of acute promyelocytic leukemia (APL) for quite a long time. It has been noticed that the sensitivity to apoptosis induced by As2O3 varies among various leukemia cells. It was reported by several groups that As2O3 could induce apoptosis in APL-derived NB4 cells at concentrations of 0.5–1 µmol/l, whereas in other leukemia cells like K562, As2O3 has no effects at the same concentration. K562 cells undergo apoptosis only when the concentration of As2O3 is greater than 2 µmol/l. Another arsenic compound, realgar (As4S4), a traditional Chinese mineral medicine, has been used to treat APL effectively and demonstrated to have lower toxicity than As2O3. It would be interesting to know whether NB4 and K562 cells will show different sensitivity to realgar as well and if there is a difference, what is the cellular mechanism of it. In our present study, K562 cells were much less sensitive than NB4 cells to apoptosis induced by realgar. We confirm that the expression of bcl-xL is significantly higher in K562 cells than that in NB4 cells and is not downregulated upon realgar treatment. K562 cells become sensitive to realgar at clinically acceptable concentrations when bcl-xL expression level is downregulated by transfecting bcl-xL antisense RNA vector into the cells. Our results suggest that the increased bcl-xL expression in K562 cells contributes to its insensitivity to realgar-induced apoptosis.