Introduction Hematopoietic stem cell transplant (HSCT) is a curative strategy for pediatric patients with high risk and relapsed Acute Lymphoblastic Leukemia (ALL), including those with Central Nervous System (CNS) involvement. There are limited data on the outcomes following HSCT in pediatric patients with ALL and CNS disease and no consensus on optimal CNS prophylaxis and treatment Methods We performed a retrospective chart review of pediatric patients who underwent HSCT for ALL from 2006-2016 at our institution. We compared outcomes for patients with CNS positive and CNS negative ALL. CNS positivity was defined as any CNS leukemic involvement either at original diagnosis of leukemia or relapse prior to HSCT. Results One hundred and thirty two patients were evaluated of which 82 (62%) were CNS negative and 50 (38%) were CNS positive. Patient and transplant characteristics were similar in both group except for disease status (Table 1). There was a higher proportion of patients with CR2/> relapse (36, 72%) in the CNS positive group compared to the CNS negative group (43, 52%) (p=0.029). Majority received myeloablative conditioning (MAC) that was TBI based in all but 3 patients. Cranial boost (CB) was given prior to HSCT to 30/50 CNS positive patient per institutional standards. Outcomes for both CNS positive and CNS negative patients were comparable (OS, DFS and Cumulative Incidence (CI) of relapse in patients that were CNS positive was 58%, 50% and 26% respectively and for CNS-negative: 68%, 66%, 23% respectively; P-values: 0.301,0.297, 0.896). In the CNS negative group, 0/23 relapses after transplant occurred in the CNS compared to 4/14 relapses in the CNS positive group. All 4 patients with CNS relapse post-transplant were in CR3 and had relapsed in the CNS at referral to HSCT. Two of the 4 received a reduced intensity regimen and 1 had not received a CB pre-HSCT due to prior CNS irradiation. Conclusion Our experience demonstrates that the outcomes after HSCT for pediatric patients with ALL with and without CNS involvement are comparable. For CNS positive patients the use of TBI-based MAC regimens with CB pre-transplant is associated with similar rates of DFS and relapse without deleterious effect on OS compared to the CNS negative group, despite a higher proportion coming to HSCT in CR2/> relapse. No additional CNS prophylaxis is required for patients that are CNS negative.