Twenty-one (5.7%) of 368 cases of acute lymphoblastic leukemia (ALL), studied fully for karyotype and immunophenotype, had breakpoints in the q23 region of chromosome 11. This abnormality resulted from reciprocal translocation in 17 cases [with chromosomes 4 (n = 5), 10 (n = 2), and variable chromosomes (n = 10)], from deletions in three cases, and from a duplication in one case. The 17 children with 11q23 translocations had higher leukocyte counts (P less than .01) and were more likely to be black (P less than .01) and younger (P = .08) as compared with each of the following non-11q23 translocation groups: t(1;19), t(9;22), random translocations, and cases without translocations. Event-free survival at 3 years for the 11q23 translocation group did not differ significantly from that of the t(1;19), t(9;22), or random translocation groups. Leukemic cells from ten of the 21 patients with an 11q23 structural chromosomal abnormality had an immunophenotype indicative of B-lineage ALL (HLA-DR+, CD19+, CD2-, CD3-); this was confirmed by the presence of rearranged immunoglobulin heavy-chain genes in seven cases. In eight of these ten B-lineage cases, the blasts were negative for expression of the CD10 antigen, indicating a primitive stage of B-cell development. Four cases were classified as T-cell ALL, and seven others were characterized by blasts that failed to react with our panel of lineage-associated monoclonal antibodies (MoAbs). Myeloid antigens were expressed by leukemic cells in three of the cases that were tested. The initial clinical features associated with translocations involving the 11q23 chromosomal region may define a distinct subtype of ALL. Whether the constellation of findings relates to a breakpoint at 11q23 per se or to the specific translocation will require further study.