In double-stranded miRNA/miRNA* duplexes, one of the strands represents an active miRNA, whereas another, known as a passenger strand (miRNA*), is typically degraded. MiR-9* is not detectable in normal myeloid cells. Here we show that miR-9* is expressed in 59% of acute myeloid leukemia (AML) cases and we investigate its clinical impact in 567 adults with de novo AML (age <= 60 years). AML cases with detectable miR-9* included a lower percentage of cases with favorable risk (P < 0.001) as compared with those with no detectable miR-9*. High levels of miR-9* expression independently predicted for higher complete remission (odds ratio = 1.28, P = 0.013) and better event-free survival (EFS) (hazard ratio (HR) = 0.86, P = 0.001), relapse-free survival (RFS) (HR = 0.84, P = 0.008) and overall survival (OS) (HR = 0.86, P = 0.002). Among the subgroup of adverse risk patients, high miR-9* expressers had strikingly longer median survival than low miR-98* expressers (EFS: 16 vs 5 months, P = 0.020; RFS: 12 vs 4, P = 0.060; OS: 23 vs 8, P = 0.021). Comparative transcriptome analysis suggests that miR-9* regulates genes involved in leukemogenesis, for example, MN1 and MLLT3. This is the first report showing that an miRNA* has prognostic value in AML.