ObjectiveThe present study aimed to investigate the correlation of protein phosphatase Mg2+/Mn2+ dependent 1D (PPM1D) with the risk stratification, treatment response, and survival profile in acute myeloid leukemia (AML) patients.MethodsTotally 221 de novo AML patients and 50 healthy donors were enrolled. The bone marrow samples were collected before treatment from AML patients and acquired after enrollment from healthy donors. And bone marrow mononuclear cells were separated for detecting the mRNA/protein expressions of PPM1D by reverse transcription‐quantitative polymerase chain reaction and Western blot. Complete remission (CR) was assessed after induction treatment, and event‐free survival (EFS) and overall survival (OS) were calculated in AML patients.ResultsPPM1D mRNA (P < .001)/protein (P < .001) relative expressions were increased in AML patients compared with healthy donors, and receiver operating characteristic curve presented that PPM1D mRNA (AUC: 0.728, 95% CI: 0.651‐0.806)/protein (AUC: 0.782, 95% CI: 0.707‐0.857) relative expressions could differentiate AML patients from healthy donors. In AML patients, PPM1D mRNA (P < .001)/protein (P < .001) high relative expressions were correlated with poor‐risk stratification. As for its association with prognosis, PPM1D mRNA (P < .001)/protein (P = .010) relative expressions were elevated in CR patients compared with non‐CR patients. Patients with PPM1D mRNA (P < .001 for EFS; P = .004 for OS)/protein (P < .001 for EFS; P = .006 for OS) high relative expressions exhibited reduced EFS and OS compared with those with low expressions.ConclusionPPM1D high expression correlates with poor‐risk stratification and might serve as a potential biomarker for worse prognosis in AML patients, suggesting its potential to guide AML management.