Objectives: Lineage switch occurs in rare leukemias, and the mechanism is unclear. We report two cases of B-lymphoblastic leukemia (B-ALL) relapsed as acute myeloid leukemia (AML). Methods: Retrospective review of clinical and laboratory data. Results: Complex cytogenetic abnormalities were detected in B-ALL for both cases with subclone heterogeneity. Postchemotherapy marrow biopsies showed trilineage hematopoiesis without detectable B-ALL. Cytogenetics in both showed stemline abnormalities. The cases were considered "occult" myelodysplastic syndrome (MDS) preceding B-ALL. The patients relapsed 6.5 and 9 months following induction, respectively. Case 1 relapsed as AML-M5 initially, was treated as such, and then relapsed again as B-ALL. Case 2 relapsed as AML-M6. Cytogenetics demonstrated persistent abnormalities. Both patients died soon after relapse. Conclusions: Lineage switch between B-ALL and AML could be intermediated by occult MDS. A pluripotent progenitor likely undergoes neoplastic transformation, resulting in a genomically unstable clone. This leads to a repertoire of heterogeneous subclones that may be selected by chemotherapy. Lineage switch heralds a dismal clinical outcome.