Graft failure may contribute to increased morbidity and mortality after allogeneic hematopoietic SCT (allo-HSCT). Here, we present risk factors for graft failure in all first allo-HSCTs performed at our center from 1995 to mid-2010 (n = 967). Graft failure was defined as >95% recipient cells any time after engraftment with no signs of relapse, or re-transplantation because of primary or secondary neutropenia (<0.5 × 109/L) and/or thrombocytopenia (<30 × 109/L). Fifty-four patients (5.6%) experienced graft failure. The majority were because of autologous reconstitution (n = 43), and only a few patients underwent re-transplantation because of primary (n = 6) or secondary (n = 5) graft failures. In non-malignant disorders, graft failure had no effect on survival, whereas in malignant disease graft failure was associated with reduced 5-year survival (22 vs 53%, P < 0.01). In multivariate analysis, ex vivo T-cell depletion (relative risk (RR) 8.82, P<0.001), HLA-mismatched grafts (RR 7.64, P < 0.001), non-malignant disorders (RR 3.32, P < 0.01) and reduced-intensity conditioning (RR 2.58, P < 0.01) increased the risk for graft failure, whereas graft failures were prevented by total nucleated cell doses of ≥2.5 × 108/kg (RR 0.36, P < 0.01). In conclusion, graft failure was only associated with inferior survival in malignant disease. Non-malignant disorders, HLA match, conditioning intensity, immunosuppression regimen and cell dose all influenced graft failure risk.