There has not been a reported series of children with therapy-induced myelodysplastic syndrome/acute myeloid leukemia (tMDS/tAML) who were treated systematically. This paper describes 24 children with tMDS/tAML who were assigned randomly to standard- or intensive-timing induction on protocol CCG 2891. Presenting features and outcomes of those children were compared with those of 960 patients with de novo MDS (62 patients) or AML (898 patients). Children with tMDS/tAML were older at presentation (P =.015), had lower white blood cell counts (P =.01), and were more likely to have MDS (21% vs 7%) (P =.02) and trisomy 8 (P =.06). Fewer had hepatomegaly (P =.02), splenomegaly (P =.03), hepatosplenomegaly (P =.02), or classic AML translocations [t(8;21), t(15;17), 16q22; P =.02]. They had a poorer induction rate (50% vs 72%, P =.016), overall survival (26% vs 47% at 3 years, P =.007), and event-free survival (21% vs 39% at 3 years, P =.023). Disease-free survival after achieving remission was similar (45% vs 53%, P =.868). Children with tMDS/tAML who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%, P =.54). In this study, the latency period to development of tMDS/tAML was the same for presumed alkylator-induced as for topoisomerase-induced myeloid leukemia. The findings of this study confirm that most children with tMDS/tAML have disease resistant to current therapies. Standard-timing induction appears less effective for this population.