We have analyzed the pretreatment 3H-thymidine labeling indices in blood and marrow blast cells from 97 children with acute lymphoblastic leukemia (ALL) and circulating blasts. The median marrow labeling index (LI) was 6.2% (range 0.8%--32.7%) and the median blood LI, 3.2% (range 0.3%--20%). Blood LI was significantly correlated with leukocyte count and rosette-forming (E+) lymphoblasts but not with central nervous system leukemia or thymic mass at diagnosis. Marrow LI was related to E+ blasts only. In children with E+ leukemia, both blood and marrow LIs were significantly higher than values for other ALL subtypes (p less than 0.01) excluding undifferentiated ALL, which was characterized by an increased blood LI. Eighteen patients had a blood LI that either equaled or exceeded the marrow LI; apart from age, the clinical features, blast phenotypes, and treatment responses of this group were similar to those of patients with blood LI less than marrow LI. Among 51 patients assessed for treatment response, the estimated median length of remission was significantly shorter for those with a blood LI greater than 4% (p = 0.002) or a marrow LI greater than 6% (p = 0.011). By Cox-regression analysis, the pretreatment proliferative activity of blood and marrow blasts, unlike other initial features studied, added significant prognostic information to leukocyte count in these patients with circulating blasts. The findings provide a cogent explanation for the differential clinical responsiveness of commonly recognized ALL subclasses.