There are limited data on the comparison of unrelated vs related peripheral blood-derived hematopoietic cell transplantation (HCT) in patients with AML and its implications in high-risk patients. In this single-center retrospective study, we report on a total of 92 consecutive patients with AML (n=87) or myelodysplastic syndrome (MDS; n=5), who were treated between 1996 and 2006 with a uniform preparative regimen of BU and CY and peripheral blood-derived HCT from related (n=46) or unrelated donors (n=46). At transplantation, 45 patients were in CR, 11 were untreated and 36 had relapsed or refractory disease. Median follow-up was 864 days after transplant (range 24-3798). At 5 years after HCT, cumulative incidences for relapse (32% of all patients) and nonrelapse mortality (NRM; 17%) were low. The 5-year relapse-free survival (RFS) and OS rates were 36 and 45% for related and 47 and 57% for unrelated patients, respectively (RFS P=0.43; OS P=0.28). High-risk patients with an unfavorable remission status before HCT benefited more from unrelated HCT than related HCT, showing a significantly better 5-year RFS of 46% (95% confidence interval (CI) 27-65) vs 22% (95% CI 4-40) (P=0.04). Unrelated HCT benefited high-risk AML patients with an unfavorable remission status better than related HCT.