Although several studies have found no change or a decreased risk of childhood cancer in twins, few have controlled for potential confounders such as birth weight. We examined the association of birth plurality and childhood cancer in pooled data from five U.S. states (California, Minnesota, New York, Texas, and Washington) using linked birth-cancer registry data. The data, excluding children with Down syndrome or who died before 28 days of life, included 17,672 cases diagnosed from 1980 to 2004 at ages 28 days to 14 years and 57,966 controls with all cases and controls born from 1970 to 2004. Analyses were restricted to children weighing ≤4,000 g at birth. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression adjusting for sex, gestational age, birth weight, birth order, maternal age, maternal race, state of birth, and birth year. Children who were multiples had no difference in risk of cancer overall (OR, 0.93; 95% CI, 0.82-1.07), but a borderline reduced risk of Wilms' tumor (OR, 0.65; 95% CI, 0.39-1.09). For children diagnosed <2 yof age there was a reduced risk of Wilms' tumor (OR, 0.27; 95% CI, 0.09-0.86) and neuroblastoma (OR, 0.46; 95% CI, 0.25-0.84) and an increased risk of fibrosarcoma (OR, 5.81; 95% CI, 1.53-22.11). Higher-order multiple birth (triplets or higher) was not associated with childhood cancer. Our analysis suggests that mechanisms other than birth weight and gestational age mayinf luence the lower risk of Wilms' tumor and neuroblastoma in multiple births.