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Second stem cell transplantation (SCT) is usually associated with high morbidity and mortality and the data on its outcome in pediatric patients with non-malignant disorders are scarce.We present 30 children with non-malignant conditions who underwent second SCT at our institution for graft failure after the first SCT; 20 had a non-malignant hematological disorder and 10 had an immune deficiency disorder. Median age at the second SCT was 6.1 years (range, 0.4-13 years) and median time from the first SCT to the second SCT was 6.2 months (range, 1.2-96 months).Twenty patients (70%) engrafted; severe acute GVHD developed in four patients (13%), and chronic GVHD developed in two patients of those at risk (10%). Thirteen deaths occurred and nine were considered treatment related. The 5-year overall (OS) and event free survival (EFS) for all patients were 53% and 47% respectively. The interval between the two transplants seemed to affect the outcome; patients who had the second SCT ≥6 months from the first SCT had better survival; the 5-year OS for the two groups (<6 months and ≥6 months) respectively were 30% and 74% (P = 0.004), and the 5-year EFS were 27% and 66% (P = 0.004). The underlying disease did not affect the outcome nor did the use of radiation in the conditioning regimen for the second SCT.Second SCT for graft failure should be considered for children with non-malignant hematological and immune deficiency disorders. Pediatr Blood Cancer 2011;56:289-293. © 2010 Wiley-Liss, Inc.