To evaluate the frequency and cytogenetic and immunophenotypic features of therapy-related, precursor B-cell acute lymphoblastic leukemia (ALL), 152 cases of immature B-cell ALL were reviewed. These were compared to the frequency of therapy-related acute myeloid leukemia (t-AML) during the same time period. Eight ALL cases with a prior diagnosis of malignancy were identified, including six (4.0%) with prior therapy considered to be therapy-related ALL (t-ALL). The t-ALL cases followed treatment for breast carcinoma (two cases), lung carcinoma (two cases), lymphocyte predominance Hodgkin's disease and follicular lymphoma with a latency period of 13 months to 8 years. All t-ALL cases had a pro-B (CD10-negative) immunophenotype with significantly higher expression of CD15 and CD65, compared to the de novo CD10-positive ALL cases. All six t-ALL cases had MLL abnormalities by fluorescence in situ hybridization, and four showed t(4;11)(q21;q23). These represented half of all 11q23-positive adult ALL cases. During the same time period, 4.9% of all AML cases were considered t-AML. There was a 16.7% frequency of 11q23 abnormalities in the t-AML group. Despite the similar frequency in therapy-related disease among ALL and AML cases, there were differences in the frequency of the diseases and t-ALL represented 12% of all therapy-related leukemias. However, t-ALL represented 46% of all 11q23-positive therapy-related leukemias. The immunogenetic features of t-ALL appear distinct and may aid in identifying more cases of this disease type in the future.