Background: The prognostic significance of miR-125b in intermediate-risk acute myeloid leukemia has not been well investigated. The aim of the study was to reveal the relationship between the elevated exosomal miR-125b level and the poor prognosis in adult patients with this disease. Methods: A total of 154 consecutive patients with intermediate-risk acute myeloid leukemia were enrolled. Exosomes were isolated from blood specimens. The exosomal miR-125b level was determined using quantitative real-time polymerase chain reaction. Patients received standardized therapy and were followed up for 1–24 months. Details about relapse and overall death were recorded. Results: Patients were divided into the high miR-125b level group (n = 77) and the low miR-125b level group (n = 77). In the multivariate Cox proportional hazard regression model, the high miR-125b level group was separately associated with increased risks of relapse and overall death in 2 years (hazard ratio [HR] 2.84, 95% CI 1.81–4.33 and HR 2.69, 95% CI 1.87–4.52). Kaplan-Meier analysis also revealed that a high miR-125b level was related to a higher cumulative relapse and overall death rates (p < 0.001 and p < 0.001, respectively). Conclusion: Circulating exosomal miR-125b concentration might be an independent prognostic indicator in intermediate-risk acute myeloid leukemia patients. An elevated miR-125b level indicated higher risks of relapse and overall death.