The present study was undertaken in an attempt to reclassify the 19 cases of childhood acute undifferentiated leukemia (AUL) diagnosed at our institution during the past 12 years. Based on ultrastructural and immunophenotypic data, seven of the cases were reclassified as lymphoid, nine as myeloid, and three remain unclassifiable. Clinical features, clonal karyotypes, and responses to treatment were also examined. Abnormal clonal karyotypes were found in 16 of 17 cases, including eight cases with translocations, three with monosomy 7 or 7q, and one with numerous complex structural rearrangements. Fourteen patients had greater than 10% French-American-British L2 blasts in bone marrow. Although nine of 15 patients who initially received induction therapy for acute lymphoblastic leukemia (ALL) achieved remission, only one patient is a long-term survivor. Only one of 10 patients who received therapy for acute nonlymphoblastic leukemia during the course of their disease remains a long-term survivor. These data suggest that the majority of cases of AUL can be reclassified as either myeloid or lymphoid leukemias, that AUL is associated with a high frequency of chromosomal abnormalities, and that AUL carries a very poor prognosis.