Sequential analysis of blast cell chromosomes in 98 cases of acute lymphoblastic leukemia (ALL) disclosed entirely different karyotypes for nine patients at the time of relapse. The presenting clinical, immunophenotypic, and cytogenetic features of this subgroup were similar to those of the 89 patients without major karyotypic shifts. The median length of initial remissions in these nine patients, all of whom received intensive multiagent therapy, was 24 months (range, 6 to 35); responses to subsequent treatment have been uniformly poor. Prominent cytogenetic changes included a gain of modal chromosome numbers in five cases, a loss of chromosomes in two, and the acquisition of an 11 q23 rearrangement in three. We propose several different mechanisms to account for these findings. In one, the presence of an entirely different ALL karyotype at relapse may represent induction of secondary leukemia analogous to the well-described entity of epipodophyllotoxin-related secondary acute myeloid leukemia (AML).