To evaluate the Quality of Life (QoL) and Social–Emotional/Behavioral functioning of survivors treated on the “Head Start I” protocol at participating medical centers across the United States between 1991 and 1997. Parents of 25 of 27 (92.5%) patients completed the Child Health Questionnaire PF-50 (CHQ), to assess their child’s QoL, along with the Behavior Assessment System for Children (BASC), to assess their social–emotional/behavioral functioning, after a mean follow-up of 5.7 years (range 13–96 months). Nineteen (76%) of the 25 parents subsequently completed the same instruments after a mean of 11.6 years (range 90–181 months), three (12%) patients died of disease and three (12%) were lost to follow-up. Mean Physical and Psychosocial QoL Summary Scores on the CHQ at Time 1 (T1) and Time 2 (T2) were within the normal range. Of the ten individual means for CHQ subscales, nine were within normal limits with the exception of Parental Emotional Impact at T1 and General Health at T2. Additionally, mean scores on the BASC at T1 and T2 were within normal limits for Externalizing and Internalizing Behaviors as well as Adaptive Skills. Serial analyses between T1 and T2 revealed non-significant changes over time with the exception of decreased General Health on the CHQ. The lack of QoL and Social–Emotional/Behavioral deficits suggests that the Head Start I protocol, involving intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue in order to avoid or delay cranial irradiation, provides encouraging pilot data warranting continued monitoring.