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Background Although pioglitazone, a well‐known anti‐diabetic agent, has recently established itself as a pillar of cancer treatment, its therapeutic value could be attenuated by the aberrant activation of the PI3K/Akt pathway. Aim To evaluate whether the PI3K/Akt suppression in leukemic cells could potentiate the anti‐leukemic effects of pioglitazone. Methods To assess the anti‐leukemic effects of PI3K/Akt inhibitors on anti‐leukemic effects of pioglitazone, we used MTT and trypan blue assays. Flow cytometric analysis and qRT‐PCR were also applied to evaluate cell cycle and apoptosis. Result The resulting data revealed that upon PPARγ stimulation in different leukemic cell lines using pioglitazone, the survival and the proliferative capacity of the cells were significantly halted. Then, we evaluated the impact of the PI3K/Akt axis on the effectiveness of the drug in the most sensitive leukemic cell line; NB4 cells. Our results showed that treatment of NB4 cells with the PI3K inhibitors increased the sensitivity of leukemic cells to pioglitazone to the degree that even lower concentrations of the agent succeeded to induce apoptotic as well as the anti‐proliferative effects. Moreover, it seems that PI3K inhibition could potentiate the anti‐leukemic effect of pioglitazone through induction of p21‐mediated sub‐G1 cell cycle arrest and altering the balance between the pro‐and anti‐apoptotic genes. Conclusion This study sheds light on the significance of the PI3K/Akt pathway in APL cell sensitivity to pioglitazone and proposed that the presence of the PI3K inhibitor in the therapeutic regimen containing pioglitazone could be promising in the treatment of this malignancy.