We asked whether minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels could identify allogeneic hematopoietic stem cell transplantation (allo- HSCT) t(8;21) (q22;q22) acute myeloid leukemia patients who are at high risk for relapse, together with the impact of c-KIT mutations. Ninety-two consecutive adult t(8;21) patients who received allo-HSCT in complete remission were enrolled. MRD status at 1, 2, and 3 months after HSCT identified relapse patients (P5.05, P < .001, P5.0001, respectively). The 2-year cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) was 32% vs 9% (P 5 .01) and 55% vs 70% (P 5 .12) for patients with and without c-KIT mutations, respectively. In multivariate analysis, MRD at the first 3 months after HSCT, rather than c-KIT mutations,was an independent factor for CIR (P5.001) and LFS(P5.001). In addition, 17 patients received donor lymphocyte infusion (DLI) as interventional therapy for MRD, and the 2-year CIR and LFS for patients with or without DLI was 24% vs 87% (P5.001) and 64%vs 0%(P < .001), respectively. In conclusion, MRD monitoring early after transplant allows further rapid identification of t(8;21) patients at high risk of relapse and was more predictive of relapse risk than c-KIT mutations.