Objectives: High birth weight has been associated with a number of childhood cancers. This study was conducted to test the hypothesis that elevated birth weight is associated with an increased risk of diagnosis- specific and age-specific groups of childhood cancers. Methods: A case- control study, using a large Children's Cancer Group database, examined birth weight all a risk factor for childhood cancer. Birth weight information for the index child was available for 3711 eases and 816 control subjects. Results: There was a statistically significant increased risk of acute lymphoblastic leukemia, Wilms' tumor, and neuroblastoma with increasing birth weight (p, trend 0.006, 0.003, and 0.001, respectively). A statistically significant decreased risk of cancer was observed for soft tissue sarcoma (p, trend = 0.04). When data were stratified on the basis of age at diagnosis, many of these associations were apparent for children whose disease was diagnosed before the age of 2 years. Moreover, for acute myeloid leukemia, age at diagnosis was an important effect modifier. For children with acute myeloid leukemia whose disease was diagnosed before 2 years of age, there was a statistically significant increased risk with high birth weight (odds ratio = 2.5, 95% confidence interval 1.1 to 5.5); there was no increased risk of acute myeloid leukemia with high birth weight noted for children whose disease was diagnosed after 2 years of age (odds ratio 1.3, 95% confidence interval 0.8 to 2.2). Conclusions: Biologic studies are needed to address why high birth weight may increase risk (particularly at younger ages) of development of certain cancers.