Large lymphoid cells containing small amounts of cytoplasmic IgM (clgM) but undetectable surface immunoglobulin (slg) have recently been recognized as precursors of B lymphocytes. They are a small, rapidly dividing pool of normal marrow lymphoblasts. Since lymphoblasts in most childhood acute lymphoblastic leukemias lack slg and other conventional B-lymphocyte and T-lymphocyte markers, we examined the possibility that some leukemias represent "pre-B"-cell neoplasms. In four of 22 consecutive patients, leukemic cells had the clgM+.slg- phenotype of pre-B cells. These patients' cells shared "common acute-lymphoblastic-leukemia" antigens and "B-cell" alloantigens, but differed in expression of several developmental features characteristic of the B-cell line. Pre-B-cell leukemias were readily responsive to chemotherapy. We conclude that a distinct subpopulation of previously unclassified leukemias reflects oncogenic transformation at the earliest recognizable stage in differentiation along the B-cell axis.