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Although arsenic trioxide (ATO) is a well-known antileukemic drug used for acute promyelocytic leukemia treatment, the development of ATO resistance is still a big challenge. We previously reported that microRNA-204 (miR-204) was involved in the regulation of acute myeloid leukemia (AML) cell apoptosis, but its role in chemoresistance is poorly understood. In the present study, we showed that miR-204 was significantly increased in AML cells after ATO treatment. Interestingly, the increased miR-204 level that was negatively correlated with ATO induced the decrease in cell viability and baculoviral inhibition of apoptosis protein repeat-containing 6 (BIRC6) expression. Overexpression of miR-204 potentiated ATO-induced AML cell growth inhibition and apoptosis. Furthermore, miR-204 directly targets to the 3′-UTR of BIRC6. Upregulation of miR-204 decreased BIRC6 luciferase activity and expression, which subsequently enhanced the expression of p53. Restoration of BIRC6 markedly reversed the effect of miR-204 on the regulation of AML cell sensitivity to ATO. Taken together, our study demonstrates that miR-204 decreases ATO chemoresistance in AML cells at least partially via promoting BIRC6/p53-mediated apoptosis. miR-204 represents a novel target of ATO, and upregulation of miR-204 may be a useful strategy to improve the efficacy of ATO in AML treatment.