Two children with acute lymphoblastic leukemia (ALL), whose lymphoblasts lacked terminal deoxynucleotidyl transferase (TdT) by both enzyme and fluorescent antibody assay, responded poorly or not at all to vincristine and prednisone. Both patients had high presenting white counts and mixed L1-L2 morphology. Lymphoblasts from one patient, an adolescent boy with a mediastinal mass, possessed surface membrane receptors for sheep red cells (E) and for complement (EAC) and had elevated adenosine deaminase activity (ADA). Lymphoblasts from a 2.5-yr- old boy without a mediastinal mass did not form E or EAC rosettes and did not express the la-like antigen or carry surface immunoglobulin. The poor response to therapy and absence of TdT were associated with a lymphoblast phenotype suggestive of a highly differentiated T-cell- derived line in one instance and an undifferentiated cell in the other instance. It is postulated that absence of TdT may predict poor therapeutic efficacy of vincristine and prednisone in acute lymphoblastic leukemia in childhood. The absence of TdT may correlate with other developmental characteristics of lymphoblasts, such as altered function or low numbers of glucocorticoid receptors or resistance to lysis by steroid drugs. Determination of many parameters of lymphoblast phenotype at diagnosis to characterize the nature of the malignant cells more precisely may ultimately enhance our understanding of, and improve therapy for, the group of leukemic children who fail to respond to standard regimens.