The incidence, clinical characteristics, and outcome of hypersensitivity reactions to teniposide (VM-26), etoposide (VP-16), or both were determined in 108 children with acute lymphoblastic leukemia (ALL) treated with a contemporary regimen of intensive multiagent chemotherapy. Fifty (46%) of the 108 patients had one or more hypersensitivity reactions. The risk of any child having an initial reaction over the cumulative dose range studied was 52% (95% confidence limits, 41% and 63%) for VM-26, compared with 34% (95% confidence limits, 24% and 44%) for VP-16. The risk of having an initial reaction to VM-26 or VP-16 was clearly related to the cumulative dose. This risk peaked at 1500 to 2000 mg/m2 for VM-26 and at 2000-3000 mg/m2 for VP-16. All reactions were Type 1 reactions according to the Gell and Coombs classification, characterized by urticaria, angioedema, flushing, rashes, or hypotension, and 86% of reactions were of Grade 1 or 2 severity according to standard criteria. There was no evidence of increasing clinical severity on repeated rechallenge with premedication, and no deaths occurred. The findings suggested that hypersensitivity reactions to epipodophyllotoxins in children with ALL are more common than previously reported, but only rarely constitute dose-limiting toxicity.