There is strong evidence that infant leukemias with a t(4;11) translocation originate in utero. To test whether other subtypes of childhood leukemias are also initiated during fetal life, we used clone-specific genetic markers for the analysis of neonatal blood spots from 5 children aged 6 months to 4 years 8 months at diagnosis of pro-B, common acute lymphoblastic leukemia (ALL), and T-ALL. In all children, the clonotypic antigen receptor gene rearrangements were already present at birth. The estimated amount of clonotypic cells was in the range of 10 to 100 cells per blood spot. In 2 infants with a t(4;11) positive ALL, we detected similar amounts of the fusion gene sequences compared with the clonal antigen receptor gene rearrangements, suggesting the presence of both markers in the same cells. Our data indicate that the first leukemogenic event of diverse types of childhood ALL may already occur in utero. (Blood. 2000;95:2722-2724)