To determine the risk and pertinent features of non-Hodgkin's lymphoma (NHL) as a second malignancy, medical records were searched of 5484 consecutive children treated for various malignancies at a single institution during a 27 year period. Of these, three have developed secondary NHL. The probability of secondary NHL in this cohort at 5 and 10 years after the diagnosis of the first malignancy was 0.05% (95% confidence interval, 0.01%, 0.2%) and at 15 years 0.16% (0.04%, 0.63%). With 30710 person-years observed, the risk in this cohort was 9.8 per 100,000 person-years. A literature search disclosed variously detailed descriptions of 21 cases of secondary NHL in patients whose primary malignancy had been diagnosed when they were less than 20 years old. Of 18 cases with documented secondary NHL histology, the most common subtypes were large cell (n = 7) and small non-cleaved cell (n = 6); mixed histology was found in three and lymphoblastic in two cases. Twenty-three of 24 children with secondary NHL had initial lymphohematopoietic neoplasms: Hodgkin's disease (n = 18), acute lymphoblastic leukemia (n = 4) and acute myelogenous leukemia (n = 1); the remaining child had astrocytoma. Of 18 patients (including three cases from this institution) with known outcome, only four were reported to be alive at 5+, 6+, 12+ and 96+ months, respectively. Secondary NHL occurs most often after therapy for Hodgkin's disease and confers a dismal prognosis.