Background:Failure of hematopoietic stem cell transplantation(HSCT) may be encountered in practicebecause of either relapse of the malignancy or dysfunction of the graft. Second HSCT may be theonly option for some patients whose initial HSCT failed. Patients and Methods:From 1991 to 2013, 321 transplants were performed at the Pediatric Blood & Marrow Transplantation Center, Chonnam National University. This study was a retrospective analysis of the medical records on 22 patients who received the secondHSCT after graft failure (GF) or relapse. Results:Among nine patients with nonmalignant diseases, seven patients had acquired AA,one had Fanconi anemia, and one had X-linked adrenoleukodystrophy (ALD). Two patients underwent the 2ndHSCT because of primary GF and sevendue to late graft rejection.Among them, seven underwent the 2ndHSCTs and twopatients underwent the 3rdsyngeneic HSCT. Stem cell sources for 2ndHSCT were matched siblings (n=4), identical twins(n=2), unrelated donors(n=2), and unrelated cord blood (UCB; n=1). All but 2 patients received stem cells from the original donor. The Kaplan-Meier (K-M) 10-year overall survival (OS) after 2nd or 3rd HSCT was 88.9% with a median follow-up of 87 months (range, 1-210), and the 10-year K-M failure-free survival was 66.7%.Among thirteen patients with malignant diseases, eight patients had acute myeloid leukemia,four had acute lymphoid leukemia, and one had chronic myelogenous leukemia. Allmalignant patients underwent second transplants because of relapses. Stem cell sources for 2ndHSCT were matched siblings (n=5), unrelated donors (n=6), unrelated cord blood (n=1), and haploidenticalmother (n=1). Six patients received stem cells from the original donor. After 2nd HSCT, five died of relapse and twoof treatment-related complications. The K-M 5-year OS was 41.0% with a median follow-up of 15 months (range, 0-128), and K-M event-free survival was 42.2%. Conclusion: Second HSCT for graft dysfunction of nonmalignant disease seems to be feasible andshould be considered as a standard practice. The relapse of malignant diseases remains a big obstacleeven after the second HSCT, although a small portion of patients might be salvaged. Further investigationof novel therapeutic strategies, as well as the understanding of the biology should be explored.