The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium Protocol 91-01 was designed to improve the outcome of children with newly diagnosed ALL while minimizing toxicity. Compared with prior protocols, post-remission therapy was intensified by substituting dexamethasone for prednisone and prolonging the asparaginase intensification from 20 to 30 weeks. Between 1991 and 1995, 377 patients (age, 0-18 years) were enrolled; 137 patients were considered standard risk (SR), and 240 patients were high risk (HR). Following a 5.0-year median follow-up, the estimated 5-year event-free survival (EFS) ± SE for all patients was 83% ± 2%, which is superior to prior DFCI ALL Consortium protocols conducted between 1981 and 1991 (P = .03). There was no significant difference in 5-year EFS based upon risk group (87% ± 3% for SR and 81% ± 3% for HR, P = .24). Age at diagnosis was a statistically significant prognostic factor (P = .03), with inferior outcomes observed in infants and children 9 years or older. Patients who tolerated 25 or fewer weeks of asparaginase had a significantly worse outcome than those who received at least 26 weeks of asparaginase (P < .01, both univariate and multivariate). Older children (at least 9 years of age) were significantly more likely to have tolerated 25 or fewer weeks of asparaginase (P < .01). Treatment on Protocol 91-01 significantly improved the outcome of children with ALL, perhaps due to the prolonged asparaginase intensification and/or the use of dexamethasone. The inferior outcome of older children may be due, in part, to increased intolerance of intensive therapy.