As a family of G protein-coupled receptors (GPCRs) with a seven-span transmembrane structure, frizzled class receptors (FZDs) play crucial roles in regulating multiple biological functions. However, their transcriptional expression profile and prognostic significance in acute myeloid leukemia (AML) are unclear. In AML, the role of FZDs was explored by performing the comprehensive analysis on the relationship between clinical characteristics and mRNA expression profiles from public databases including cBioPortal for Cancer Genomics, Gene Expression Profile Interactive Analysis (GEPIA), and Cancer Cell Line Encyclopedia (CCLE). We identified that in the majority of 27 AML cell lines, frizzled class receptor 6 (FZD6) was high-expressed. A significantly higher expression of FZD6 in AML patients was observed when compared to normal controls ( P < 0.01 ). Compared with intermediate and poor/adverse risk group patients, FZD6 expressed much lower in cytogenetic favorable risk group patients ( P < 0.0001 ). Patients with higher-expressed FZD6 were associated with shorter overall survival (OS) ( P = 0.0089 ) rather than progression-free survival (PFS). However, the predictive effect of FZD6 on OS could be reversed by hematopoietic stem cell transplantation (HSCT). The data of gene set enrichment analysis (GSEA) demonstrated that 4 gene sets, including MYC targets, HEME metabolism, E2F targets, and UV response, were differentially enriched in the high-expression FZD6 group. To conclude, the study suggested that high expression of FZD6 might be a novel poor prognostic biomarker for AML treatment.