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Background: Acute myeloid leukemia (AML) is a heterogeneous group of hematologic malignancies with great variability in the pathogenesis and clinical course. DNA methylation of CpG islands within the promoters of specific genes may play roles in tumor initiation and progression. Secreted frizzled-related proteins (SFRPs) are negative regulator of the Wnt signaling pathway. In the present study, we compared the methylation status of SFRP1 and SFRP2 genes promoter in patients with AML and healthy individuals. Methods: In peripheral blood from 43 patients afflicted with de novo AML and 25 healthy controls, isolated DNA was treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction (MSP) with primers specific for methylated and unmethylated promoter sequences of the SFRP1 and SFRP2 genes. We used Mann-Whitney u-tests to investigate the correlation between SFRP1 and SFRP2 genes hypermethylation and clinical parameters. Findings: The frequency of aberrant hypermethylation of SFRP1 and SFRP2 genes promoter in patients with AML was determined 30.2% (13/43) and 20.9% (9/43), respectively. In addition, for all subjects in control group, methylation of SFRP1 and SFRP2 genes promoter were negative. Patients with M0 subtype of FAB-AML had the highest incidence of hypermethylation of SFRP1 (P = 0.028) and SFRP2 (P = 0.004) genes promoter. Conclusion: The present study showed that, like many solid tumors, SFRPs genes methylation also occurs in AML. Therefore, the methylation of these genes may play a role in leukemogenesis initiation.