The prognosis of patients with relapsed acute myeloid leukemia after allogeneic transplantation is poor. We hypothesized that initial disease control by effective cytoreduction, followed by rapid induction of a profound allo-immune response by donor-lymphocyte infusion during the neutropenic phase, is essential for long-term survival. Additional interferon-α was administered when no acute graft-versus-host-disease occurred within 3 weeks after donor-lymphocyte infusion. Overall, 44 patients with relapsed acute myeloid leukemia were assessed; 26 had relapsed after myeloablative conditioning and 18 after reduced-intensity conditioning. Of these 44 patients, seven were not eligible for cytoreductive treatment because of poor performance status (n= 3) or severe graft-versus-host-disease (n= 4) at the time of relapse. Patients with smoldering relapses (n= 5) received donor-lymphocyte infusion only. Thirty-two patients received cytoreductive treatment, followed by donor-lymphocyte infusion in 22 patients. Reasons for not receiving donor-lymphocyte infusion were chemotherapy-related death (n= 1) and chemotherapy-refractory disease (n= 9). The 2-year overall survival rate after donor-lymphocyte infusion was 36%(95% confidence-interval: 16–57%). The impact of acute graft-versus-host-disease on survival was calculated with a Cox-regression model including onset of acute graft-versus-host-disease as a time-dependent variable. Development of grade 1–3, but not grade 4, acute graft-versus-host-disease was associated with superior survival as compared to absence of graft-versus-host-disease (hazard ratio 0.22, P= 0.03). In conclusion, efficient cytoreduction followed by donor-lymphocyte infusion and subsequent interferon-α leading to limited acute graft-versus-host-disease represents a potentially curative option for patients with relapsed acute myeloid leukemia after allogeneic transplantation.