Background: Wnt signaling is a critical pathway for the development of acute myeloid leukemia (AML). Some studies have evaluated the expression or methylation of secreted frizzled-related protein 2 (SFRP2) as an antagonist and beta-catenin (β-catenin) as a critical mediator of this pathway. Since we found no comprehensive study on these genes in Iran, we aimed to investigate the status of both SFRP2 expression and methylation, and also β-catenin expression, in conjunction with clinical characteristics, in Iranian patients with de novo non-M3 AML.Methods: The methylation and expression of SFRP2 were determined in 188 patients with primary non-M3 AML and 60 healthy controls, who were referred to Shariati Hospital, Tehran, Iran, between January 2017 and February 2019. The methylation-specific polymerase chain reaction (PCR) and real-time quantitative PCR were used, respectively. The expression of β-catenin was explored via real-time quantitative PCR. Statistical analysis was performed using the Mann–Whitney U test (SPSS software, version 23). A P value of less than 0.05 (2-tailed) was considered significant.Results: SFRP2 mRNA showed a significant decline in the AML group compared with the controls (p