BACKGROUND Acute myeloid leukemia (AML) is a common hematologic malignancy of adults. The pathophysiological mechanism of AML is not well understood. The purpose of this study was to examine the crucial miRNAs and mRNAs associated with AML survival. MATERIAL AND METHODS The full clinical dataset of miRNA and mRNA expression profiling of AML patients was downloaded from The Cancer Genome Atlas database. Univariate Cox regression analysis was performed to obtain those miRNAs and mRNAs associated with AML survival. A miRNA-mRNA interaction network was constructed. The underlying functions of mRNAs were predicted through Kyoto Encyclopedia of Genes and Genomes (KEEG) pathway enrichment. The expression levels of miRNAs and mRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS Fourteen miRNAs and 830 mRNAs associated with AML survival were identified. Of the 14 miRNAs, hsa-mir-425, hsa-mir-1201, and hsa-mir-1978 were identified as risk factors and the other 11 miRNAs were identified as protective factors of AML survival. For target-genes of miRNAs, GTSF1, RTN4R, and CD44 were the top risk factor target-genes associated with AML survival. An interaction network was constructed that including 607 miRNA-target gene pairs associated with AML survival. Target-genes associated with AML survival were significantly enriched in several pathways including pancreatic secretion, calcium signaling pathway, natural killer cell mediated cytotoxicity, and Alzheimer's disease. The qRT-PCR results were consistent with our bioinformatics analyses. CONCLUSIONS The miRNA hsa-mir-425 was identified as the top risk factor miRNA of AML survival and CD44 was identified as one of the top three risk factor target-genes associated with AML survival. Both hsa-mir-425 and CD44 may play key roles in progression and development of AML through calcium signaling pathway and natural killer cell mediated cytotoxicity.