Thirty-two cases of neurofibromatosis Type I (NF1) were identified among 6,678 pediatric cancer patients treated at St. Jude Children's Research Hospital over a 29-year period. A total of 35 malignant neoplasms have been diagnosed in these patients. Two of three patients with second malignant neoplasms had colon cancer at the primary or second tumor. Of particular interest are two cases in which both NF1 and malignant peripheral nerve sheath tumors were present in multiple successive generations: a patient with colon cancer and non-Hodgkin lymphoma who has a constitutional abnormality of the p53 gene, and a patient with acute lymphoblastic leukemia with the Philadelphia chromosome and other cytogenetic abnormalities, including the t(8;14). Outcome of patients in the largest subgroup, that of malignant peripheral nerve sheath tumors, was favorable only for those patients having resectable extremity lesions. In contrast, all patients with central nervous system tumors are surviving. These cases reflect the molecular and cytogenetic abnormalities that can be present in NF1 and the variety of tumors that may result in these patients.