Two unusual cases of acute lymphoblastic leukemia-hand mirror variant (ALL-HMV) are presented. One patient demonstrated a mixed immunophenotype with HLA-DR, My7, transferrin receptor surface markers, and terminal deoxynucleotidyl transferase positivity. To the authors' knowledge, this is the first ALL-HMV reported with myeloid antigen. The patient died during induction and did not demonstrate the indolent course noted in the female subgroup with this disorder. The second case initially was not an ALL-HMV but presented as a non-T non-B ALL, and the patient had a relapse six years later with numerous hand mirror cells (HMCs). In the authors' experience, this is the first case of ALL that presented as a non-HMC and relapsed as an ALL-HMV. The patient's immunophenotype revealed he was HLA-DR, transferrin receptor, and TdT positive. Both patients' leukemic cells showed a diffuse granular periodic acid-Schiff on a clear background and acid phosphatase-positive pattern. Immunogenetics revealed a clonal rearrangement of one of the two Ig heavy chain loci in the one patient evaluated. Western blot analysis of the bone marrow plasma of both patients with ALL-HMV showed an increase of cross-reactive IgG to the envelope gp70 and IgM against the core p30 proteins of the baboon endogenous virus (BaEV) and simian sarcoma-associated virus (SSAV). Furthermore, their bone marrow plasma demonstrated IgM antibodies to the gp70 that were not present in any of the other non-hand mirror leukemic patients or the normal controls. These findings strengthen the concept that HMCs in ALL are formed in relation to an immunologic response to increased proteins related to BaEV and/or SSAV.