Chemotherapy resistance from imbalanced apoptosis regulation may contribute to poor outcome in leukaemias with t(4;11). Anti‐apoptotic BCL‐2 expression and target modulation were characterized in cell lines with t(4;11) and BCL‐2 expression was examined in MLL and non‐MLL infant/paediatric leukaemia cases by Western blot analysis and/or real‐time polymerase chain reaction. Cytotoxicity of Genasense™ (Oblimersen Sodium, G3139) alone or combined with cytotoxic drugs was assessed by MTT [(3‐4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide] assays of the cell lines, applying pharmacostatistical response surface modelling of drug interactions. Apoptosis and cell cycle were evaluated by flow cytometry in RS4:11 cells. Primary leukaemias and cell lines with t(4;11) expressed abundant BCL2 mRNA and protein. Variable, sometimes substantial BCL2 mRNA was detected in other leukaemia subtypes. G3139 reduced BCL2 mRNA and protein in RS4:11 cells. The most sensitive cell line to single‐agent G3139 was RS4:11. Low G3139 concentrations sensitized RS4:11 and MV4‐11 cells to select anti‐leukaemia cytotoxic drugs. In RS4:11 cells, combining G3139 with doxorubicin (ADR) increased active caspase 3 and TUNEL staining compared to ADR alone, indicating greater apoptosis, and G3139 increased S‐phase progression. The abundant BCL‐2 affords a molecular target in leukaemias with t(4;11). G3139 exhibits preclinical activity and synergy with select cytotoxic agents in RS4:11 and MV4‐11 cells, and these effects occur through apoptosis.