We studied 232 consecutive children transplanted between 1990 and 2011 with relapse after first hematopoietic cell transplant (HCT). Kaplan-Meier survival and hazard ratios for mortality were calculated for factors known at time of relapse using Cox proportional hazards models. The median (range) age at time of first HCT was 10.9 (0.5-20.9) years, time to relapse was 6.1 (0.2-89.5) months after HCT, and age at relapse was 11.7 (0.7-23.6) years. The 3-year overall survival (OS) after relapse was 13% (95% confidence interval (CI): 9%, 18%).The median (range) follow-up for the 18 surviving patients was 7.2 (3.0-24.4) years after relapse. The remaining 214 died after a median of 3 months (0.02-190.4). OS was not significantly different for patients with ALL as compared to AML. Fifty-one patients proceeded to second transplant of whom nine survive. Factors associated with improved survival included late relapse (>12 months), ALL in first CR at the time of first transplant and chemotherapy-based first conditioning regimens. These results can be used to counsel patients at the time of relapse after first transplant and as a baseline for comparison as to the effectiveness of newer therapies which are greatly needed for treatment of post-transplant relapse.