Core binding factor (CBF) AML with the D816 C-KIT gene mutation demonstrate inferior treatment outcomes. However, the remaining cases without the D816 C-KIT mutation imply a requirement of more sophisticated dissection of the patients according to their prognosis. In this study, we analyzed the prognostic value of a single nucleotide polymorphism array (SNP-A) based karyotyping combined with metaphase cytogenetics (MC) to facilitate further stratification of CBF AML patients. A total of 98 CBF AML patients were included and genome-wide Human SNP 6.0 Arrays (Affymetrix) were performed using marrow samples taken at diagnosis. Overall, 40 abnormal lesions were identified in 25 patients (26%). Survival of the patients with the abnormal lesion(s) detected by SNP-A and/or MC was worse than those without lesions in terms of the 2-year overall survival (OS; 57.5% vs. 76.4%, P = 0.028), event-free (EFS; 45.7% vs. 66.2%, P = 0.072), and leukemia-free survival (LFS; 49.0% vs. 77.4%, P = 0.015), specially in the subgroup with inv(16)/t(16;16) (40.9% vs. 80.2% OS, P = 0.040) and in the subgroup without the D816 C-KIT mutation (61.6% vs. 82.7% OS, P = 0.038). Multivariate analysis confirmed the prognostic impact of the abnormal SNP-A and/or MC lesion on EFS (HR 2.011, P = 0.047), and LFS (HR 3.231, P = 0.005) in the overall CBF AML. This study suggests that the combined use of SNP-A with MC in the CBF AML can provide important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without the D816 C-KIT mutation.