Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in children. It has minimal bone marrow toxicity. Its major side effects are anaphylaxis, pancreatitis, diabetes, coagulation abnormalities, and thrombosis, especially intracranial. It is derived from 2 different sources: Escherichia coli and Erwinia chrysanthemi. Nonrandomized clinical studies have suggested a similar efficacy of these 2 types of asparaginases and a lower toxicity for Erwinia-asparaginase. The European Organisation for Research and Treatment of Cancer–Children's Leukemia Group (EORTC-CLG) 58881 trial randomized 700 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to eitherE coli– or Erwinia-asparaginase at the same dosage of 10 000 IU/m² twice weekly to compare toxicity and efficacy. Coagulation abnormalities were more frequent in theE coli–asparaginase than in theErwinia-asparaginase arm of the study (30.2% versus 11.9%, P < .0001). The incidence of other toxicity was not significantly different. In the Erwinia-asparaginase arm, more patients failed to achieve complete remission (4.9% versus 2.0%; P = .038) and the relapse rate was higher, leading to shorter event-free survival (hazard ratio,1.59; 95% CI, 1.23-2.06; P = .0004). The estimate of event-free survival rate (SE) at 6 years was 59.8% (2.6%) versus 73.4% (2.4%). Overall survival rate at 6 years was also lower in theErwinia-asparaginase arm at 75.1% (2.3%) versus 83.9% (2.0%), P = .002. With the dose scheduling used in this protocol, E coli–asparaginase induced more coagulation abnormalities but was superior toErwinia-asparaginase for the treatment of childhood lymphoid malignancies.