We studied induction of apoptosis in several human malignant B cells from chronic lymphocytic leukemias (BCLL) by triggering the APO‐1 antigen. The APO‐1 antigen was found to be expressed on the surface of malignant B cells. In BCLL cells from most patients, APO‐1 antigen expression increased following in vitro activation by Staphylococcus aureus Cowan I (SAC) or interleukin‐2 (IL‐2). In certain cases of BCLL co‐stimulation with SAC plus IL‐2 resulted in a synergistic up‐regulation of the APO‐1 antigen on the cell surface and prepared BCLL cells for monoclonal antibody anti‐APO‐1 mediated apoptosis. Interestingly, bcl‐2 mRNA expression decreased upon stimulation with SAC plus IL‐2, whereas SAC or IL‐2 alone did not affect the level of bcl‐2 expression. Thus, in these BCLL cells induction of anti‐APO‐1‐mediated apoptosis appeared to be correlated with bcl‐2 mRNA down‐regulation. One informative BCLL, however, with a similar pattern of APO‐1‐antigen expression, did not show SAC plus IL‐2‐dependent bcl‐2 down‐regulation. Surprisingly, these cells proliferated in response to anti‐APO‐1 only when cells were co‐stimulated with SAC plus IL‐2. Our data suggest that down‐regulation of bcl‐2 prepares BCLL cells for induction of APO‐1‐mediated apoptosis. In addition they demonstrate that triggering of the APO‐1 antigen may also lead to the induction of proliferation in special cases of BCLL.