The t(9;11)(p21;q23) has been associated with characteristic clinical features and a superior treatment outcome in previously untreated pediatric acute myeloblastic leukemia (AML), but has not been well studied in children with secondary AML. This translocation was detected in 6.7% of de novo and 46% of secondary AML patients treated at St Jude Children's Research Hospital over an 11-year period. Clinical, immunophenotypic, and morphologic characteristics were examined for the cases of t(9;11) secondary AML (n = 12) and compared with findings for children with t(9;11) de novo AML (n = 12). Patients with t(9;11) secondary AML were older at diagnosis, had higher hemoglobin levels, and central nervous system leukemia or hepatosplenomegaly was less frequent. These differences probably reflect survival of the first malignancy and close clinical scrutiny during post-treatment follow-up. Whereas the t(9;11)(p21;q23) occurred exclusively in the French-American-British (FAB) M5 subtype in de novo AML, the FAB M0 and M4 subtypes were also represented in secondary cases. The complete remission rate was somewhat higher for the de novo AML group (91 vs 58%; p = 0.16); their event-free survival was clearly superior to that for children with t(9;11) secondary AML (p = 0.003). Host differences related to the previous malignancy or its treatment could explain the poorer clinical outcome for patients with t(9;11) secondary AML. Alternatively, there could be critical differences at the translocation site or additional, hidden molecular events, that explain the different outcomes.