Early response to therapy, typically assessed by bone marrow status, is predictive of outcome in childhood acute lymphoblastic leukemia (ALL). Less is known about the significance of early clearance of blast cells in peripheral blood. We reviewed medical records of all patients with ALL enrolled on St Jude Total Therapy Study XI (February 1984 to September 1988) to determine the presence of blast cells in peripheral blood at diagnosis and after 1 week of intensive induction therapy. Of the 358 patients, 59 lacked evidence of circulating blast cells at diagnosis, and data were unavailable for 2 patients. The prognostic significance of persistent circulating blast cells in the remaining 297 patients was assessed in a multivariate analysis that included known adverse prognostic factors. Persistent circulating leukemic blasts were present at day 8 in 41 patients (14%). Compared with the “blast- negative” group, these patients had a significantly higher frequency of several adverse clinical features (leukocyte count > 50 x 10(9)/L, mediastinal mass, central nervous system leukemia, T-cell phenotype, lack of CD10 expression, and L2 morphology) and a significantly poorer 5-year event-free survival (34% +/- 8% [SE] v 77% +/- 3%, P < .01). By multivariate analysis, blast cell persistence at week 1 was the most significant adverse feature in the overall cohort (relative risk, 2.9; 95% confidence interval, 1.8 to 4.8) and in an analysis limited to B- lineage cases (relative risk, 3.6; 95% confidence interval, 1.9 to 7.1). Patients identified by this simple, noninvasive measure may benefit from early modification of therapy.