AbstractGenerating accurate prognoses is extremely important for treating patients with cancer. Prognostic prediction based on messenger RNA (mRNA) expression has shown superior clinical value to other markers for some cancers but is not currently used for acute myeloid leukemia (AML). Lipid metabolism is associated with biological aspects of cancer progression, including massive proliferation, and abnormal signaling. Moreover, abnormalities in lipid metabolism have prognostic significance. Patients with AML display abnormalities in sphingolipid metabolism and fatty acid oxidation. TPD52 is a regulator of lipid metabolism and plays a role in the formation of lipid droplets and fatty acid storage. Although the prognostic significance of TPD52 expression has been reported for many types of cancer, it has not yet been assessed in patients with AML. Therefore, the aim of the current study was to assess the prognostic significance of TPD52 in AML using three independent AML cohorts: one from The Cancer Genome Atlas (TGCA; n = 142) and two from the National Center for Biotechnology Information: GSE12417 (GPL96‐97; n = 162) and GSE12417 (GPL570; n = 78). TPD52 was found to be overexpressed in patients with AML (GSE84881; n = 23). The Kaplan‐Meier curve revealed that TPD52 overexpression was associated with a poor prognosis for patients with AML with good discrimination ( P = 0.013, P = 0.005, and P = 0.032 for the TGCA, GSE12417, and GSE12417, respectively). Analysis of C‐indices and area under the receiver operating characteristic curve values further supported this discriminative ability. Moreover, multivariate analysis confirmed the prognostic significance of TPD52 expression levels ( P = 0.0196). These results suggest that the TPD52 mRNA level is a potential biomarker for AML.