The prognostic importance of T-lineage acute lymphoblastic leukemia (ALL) in contemporary programs of intensive chemotherapy has been controversial. We therefore assessed the impact of this biological feature in risk-adjusted frontline chemotherapy studies of the Children's Cancer Group (CCG), conducted from 1983 to 1994. A substantially greater proportion of T-lineage patients (N = 730) presented with poor-risk features as compared to B-lineage patients (N = 3668) treated in the same studies (71.1% vs. 39.7%, P < 0.0001). Consequently, in the CCG-100 series of clinical trials (1983-1989), which tested regimens that were largely of moderate intensity, T-lineage ALL patients had an excess of adverse early events compared to patients in the B-lineage group: 3-year event-free survival (EFS) estimate, 65.8% vs 78.2% (P < 0.0001). With the introduction of more intensive chemotherapy in studies from 1989 to 1994 (CCG-1800 series). We observed a progressive and significant improvement in the clinical outcome of patients with T-lineage immunophenotype. Three- and 5-year EFS probabilities increased from 65.8% to 78.1% and from 61.0% to 75.2%, respectively, becoming comparable to or slightly better than results for B-lineage ALL patients. When adjusted for the competing effects of leukocyte count, age, organomegaly and other poor-risk features, T-lineage immunophenotype showed no important impact on the overall EFS pattern. These findings demonstrate the loss of adverse prognostic by T-lineage ALL in a large program of intensive chemotherapy developed over the past decade.