Results were analyzed for 48 consecutive patients with acute myeloid leukemia not in remission who underwent unrelated donor bone marrow or stem cell transplantation between 1991 and February 2003 at 2 transplant centers. Forty-six were adults with a median age of 32 years (range, 4-58 years). Forty-two were HLA-A, -B, and -DR matched with their respective donors, and 6 were mismatched at 1 of these loci. The conditioning regimen was myeloablative in all cases: busulfan/cyclophosphamide/etoposide in 34 patients, busulfan/cyclophosphamide in 10 patients, and total body irradiation based in 4 patients. Median follow-up for survivors was 540 days (range, 145-2716 days). Only patients with <5000 peripheral blood blasts per microliter at the time of transplantation survived 2 years (18% versus 0%; P = .003). Similarly, patients with <20% blasts in the marrow at the time of transplantation had superior 2-year survival compared with those who had > or =20% (33% versus 5%; P = .04). Patients with <20% blasts who had > or =3 prior therapies also fared poorly. Cause of death was more commonly treatment related rather than relapse related. This study confirms that patients with acute myeloid leukemia not in remission can achieve prolonged survival with myeloablative conditioning and unrelated donor cell transplantation. However, sustained survival occurs only in patients with a low disease burden at the time of unrelated donor stem cell transplantation, and patients with a high disease burden may benefit from added counseling regarding the high risk of death due to both treatment-related toxicities and disease relapse.