The objectives of our study were to quantify risks for developing new malignancies among childhood cancer survivors, identify links between particular types of first and subsequent cancer, and evaluate the possible role of treatment. A cohort of 25,965 2-month survivors of childhood cancer diagnosed in the U.S. during 1973–2002 was identified and followed through SEER cancer registries. Observed-to-expected ratios (O/E) were calculated, and Poisson regression was used to compare risks among treatment groups. Childhood cancer survivors were at nearly 6-fold risk of developing a new cancer relative to the general population (O/E = 5.9, 95% CI: 5.4–6.5). Most common were subsequent primary cancers of the female breast, central nervous system, bone, thyroid gland and soft tissue, as well as cutaneous melanoma and acute non-lymphocytic leukemia (ANLL). The greatest risks of subsequent cancers occurred among patients diagnosed previously with Hodgkin lymphoma (HL), Ewing sarcoma, primitive neuroectodermal tumor, or retinoblastoma. Risk of subsequent solid cancers was higher among persons whose initial treatment for childhood cancer included radiotherapy, whereas the excess of subsequent ANLL was strongly related to chemotherapy. The O/E for subsequent ANLL increased with increasing calendar year of initial cancer diagnosis among survivors of cancers other than HL, most likely due to increasing use of leukemogenic drugs for solid cancers and non-Hodgkin lymphoma. Childhood cancer survivors are at markedly increased risk of developing a variety of new cancers relative to the general population, but the magnitude of excess risk and specific types of second cancer vary widely by type of first cancer. © 2007 Wiley-Liss, Inc.