The only two children of clinically healthy parents both developed an acute lymphocytic leukemia of the T-cell type, one with a mediastinal mass, one without. Extensive laboratory studies revealed a combination of the following unusual circumstances. (1) The injection of leukemic bone marrow into BALB/c-nu/nu mice led to an explosive simultaneous development of disseminated lymphomatous tumors with murine karyotype. (2) HLA typing and MLC testing of all four family members revealed sharing of HLA-A,D and DRw determinants between the parents and pointed to the appearance of suppressor cell activity with the outbreak of the acute leukemia of one sibling. (3) Parental lymphocytes gave a low response to mitogen stimulation, suggesting a subclinical cellular immune defect. It is proposed that the siblings inherited from each parent a defective immune response factor, possibly related to HLA-D/DRw antigens, that predisposed to acute T-cell leukemia. The neoplastic process might have been triggered by a transferable agent.