We performed a retrospective review of the events and outcome for DS patients enrolled on CCG study 1891, a randomized clinical trial open 1990–1993 for children less than 10 years old with IR newly diagnosed ALL. Of the 1204 eligible patients enrolled, 33 (2.7%) patients had DS. DS patients were randomized in an identical manner to other enrolled patients to one of three treatment regimens: single delayed intensification (single DI), double DI, or single DI with intensified pulses of vincristine/prednisone during maintenance. This trial demonstrated an improved EFS at 6 years of 79% for the overall study group that was randomized to the double DI arm. A separate subset analysis of survivorship in the DS patients was performed using the STATA program and then compared to the Non-Downs Syndrome (NDS) study patients. 14/33 (42%) DS patients had a M1 marrow on Induction Day 7 while 19/33 (58%) DS patients had an Induction Day 7 bone marrow of M2 or M3 status. Of these 19 DS patients with slow early response, 9/19 (47%) went on to have serious events ( 3 induction failures, 3 relapses, 2 septic deaths, 1 CNS hemorrhage) compared to 2/14 (14%) rapid responders with DS that had events ( 1 relapse, 1 septic death). DS patients that had an M2 or M3 marrow response on Induction Day 7 had more adverse events than their NDS patient cohort with the same M2 or M3 bone marrow response. (p=0.02) DS patients who achieved M1 marrow status on Day 7 demonstrated a similar number of events as NDS patients with the same bone marrow response. (p=0.83) Detailed chart review demonstrated that congenital anomalies (cardiac, gatrointestinal) did not account for the greater risk of adverse events in these DS patients: 10/33 DS patients had congenital anomalies but none of these patients relapsed and only 1 died. Of all 8 patient deaths in the DS subset ( rapid and slow responders), 3 were sepsis related deaths in remission while 4 were due to relapse and 1 due to hemorrhage. Remission induction for the DS patients was 91% ( 30/33 with M1 marrow at Day 29 of Induction) compared to 98% for the overall study cohort. There was a 9% (3/33) induction failure rate; two of these three patients went into remission with an off study re-induction and have had long term disease free survival. Efficacy of the three treatment regimens in the DS patients, as measured by EFS and survival, mirrored that of the general study population. Although the DS patient numbers are small, it appears that an intensified therapy regimen provides benefit to DS patients similar to their NDS cohort. With the intensified therapy, DS patients may derive a similar improved benefit from very aggressive supportive care as a potential means of decreasing fatal sepsis and bleeding events.